Full text data of CLU
CLU
(APOJ, CLI, KUB1)
[Confidence: high (present in two of the MS resources)]
Clusterin (Aging-associated gene 4 protein; Apolipoprotein J; Apo-J; Complement cytolysis inhibitor; CLI; Complement-associated protein SP-40,40; Ku70-binding protein 1; NA1/NA2; Testosterone-repressed prostate message 2; TRPM-2; Clusterin beta chain; ApoJalpha; Complement cytolysis inhibitor a chain; Clusterin alpha chain; ApoJbeta; Complement cytolysis inhibitor b chain; Flags: Precursor)
Clusterin (Aging-associated gene 4 protein; Apolipoprotein J; Apo-J; Complement cytolysis inhibitor; CLI; Complement-associated protein SP-40,40; Ku70-binding protein 1; NA1/NA2; Testosterone-repressed prostate message 2; TRPM-2; Clusterin beta chain; ApoJalpha; Complement cytolysis inhibitor a chain; Clusterin alpha chain; ApoJbeta; Complement cytolysis inhibitor b chain; Flags: Precursor)
hRBCD
IPI00291262
IPI00291262 Clusterin precursor Clusterin precursor membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 2 n/a n/a extracellular binds RBC n/a found at its expected molecular weight found at molecular weight
IPI00291262 Clusterin precursor Clusterin precursor membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 2 n/a n/a extracellular binds RBC n/a found at its expected molecular weight found at molecular weight
UniProt
P10909
ID CLUS_HUMAN Reviewed; 449 AA.
AC P10909; B2R9Q1; B3KSE6; P11380; P11381; Q2TU75; Q5HYC1; Q7Z5B9;
read moreDT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1989, sequence version 1.
DT 22-JAN-2014, entry version 164.
DE RecName: Full=Clusterin;
DE AltName: Full=Aging-associated gene 4 protein;
DE AltName: Full=Apolipoprotein J;
DE Short=Apo-J;
DE AltName: Full=Complement cytolysis inhibitor;
DE Short=CLI;
DE AltName: Full=Complement-associated protein SP-40,40;
DE AltName: Full=Ku70-binding protein 1;
DE AltName: Full=NA1/NA2;
DE AltName: Full=Testosterone-repressed prostate message 2;
DE Short=TRPM-2;
DE Contains:
DE RecName: Full=Clusterin beta chain;
DE AltName: Full=ApoJalpha;
DE AltName: Full=Complement cytolysis inhibitor a chain;
DE Contains:
DE RecName: Full=Clusterin alpha chain;
DE AltName: Full=ApoJbeta;
DE AltName: Full=Complement cytolysis inhibitor b chain;
DE Flags: Precursor;
GN Name=CLU; Synonyms=APOJ, CLI, KUB1; ORFNames=AAG4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF
RP N-TERMINUS, SUBUNIT, DISULFIDE BONDS, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Liver;
RX PubMed=2780565; DOI=10.1073/pnas.86.18.7123;
RA Jenne D.E., Tschopp J.;
RT "Molecular structure and functional characterization of a human
RT complement cytolysis inhibitor found in blood and seminal plasma:
RT identity to sulfated glycoprotein 2, a constituent of rat testis
RT fluid.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:7123-7127(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], PARTIAL NUCLEOTIDE SEQUENCE [MRNA]
RP (ISOFORM 2), AND TISSUE SPECIFICITY.
RX PubMed=8181474; DOI=10.1111/j.1432-1033.1994.tb18807.x;
RA Wong P., Taillefer D., Lakins J., Pineault J., Chader G.,
RA Tenniswood M.;
RT "Molecular characterization of human TRPM-2/clusterin, a gene
RT associated with sperm maturation, apoptosis and neurodegeneration.";
RL Eur. J. Biochem. 221:917-925(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND PARTIAL
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Stomach, and Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RA Li W.B., Gruber C., Jessee J., Polayes D.;
RT "Full-length cDNA libraries and normalization.";
RL Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Small intestine;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS HIS-317; ASN-328 AND
RP LEU-396.
RG NIEHS SNPs program;
RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S.,
RA Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A.,
RA Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X.,
RA Allen N.R., Anderson S., Asakawa T., Blechschmidt K., Bloom T.,
RA Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K.,
RA DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G.,
RA Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B.,
RA Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C.,
RA O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K.,
RA Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R.,
RA Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K.,
RA Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q.,
RA Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N.,
RA Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5), AND PARTIAL
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain, and Spinal ganglion;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP PROTEIN SEQUENCE OF 23-33; 229-242; 303-317 AND 397-403, SUBUNIT, AND
RP INTERACTION WITH APOA1.
RX PubMed=1903064;
RA James R.W., Hochstrasser A.-C., Borghini I., Martin B.M., Pometta D.,
RA Hochstrasser D.F.;
RT "Characterization of a human high density lipoprotein-associated
RT protein, NA1/NA2. Identity with SP-40,40, an inhibitor of complement-
RT mediated cytolysis.";
RL Arterioscler. Thromb. 11:645-652(1991).
RN [10]
RP PROTEIN SEQUENCE OF 23-52 AND 228-257, SUBUNIT, DISULFIDE BOND,
RP PROTEOLYTIC PROCESSING, GLYCOSYLATION, SUBCELLULAR LOCATION, AND
RP TISSUE SPECIFICITY.
RX PubMed=2387851;
RA de Silva H., Stuart W.D., Park Y.B., Mao S.J.T., Gil C.M.,
RA Wetterau J.R., Busch S.J., Harmony J.A.K.;
RT "Purification and characterization of apolipoprotein J.";
RL J. Biol. Chem. 265:14292-14297(1990).
RN [11]
RP PROTEIN SEQUENCE OF 23-41 AND 228-246, INTERACTION WITH APP,
RP SUBCELLULAR LOCATION, DISULFIDE BOND, AND TISSUE SPECIFICITY.
RX PubMed=8328966;
RA Ghiso J., Matsubara E., Koudinov A., Choi-Miura N.-H., Tomita M.,
RA Wisniewski T., Frangione B.;
RT "The cerebrospinal-fluid soluble form of Alzheimer's amyloid beta is
RT complexed to SP-40,40 (apolipoprotein J), an inhibitor of the
RT complement membrane-attack complex.";
RL Biochem. J. 293:27-30(1993).
RN [12]
RP PROTEIN SEQUENCE OF 23-37 AND 228-242.
RX PubMed=2601725; DOI=10.1016/0161-5890(89)90139-9;
RA Choi N.H., Mazda T., Tomita M.;
RT "A serum protein SP40,40 modulates the formation of membrane attack
RT complex of complement on erythrocytes.";
RL Mol. Immunol. 26:835-840(1989).
RN [13]
RP PROTEIN SEQUENCE OF 23-33 AND 228-240, SUBCELLULAR LOCATION, AND
RP TISSUE SPECIFICITY.
RX PubMed=3154963;
RA Hochstrasser A.-C., James R.W., Martin B.M., Harrington M.,
RA Hochstrasser D.F., Pometta D., Merril C.R.;
RT "HDL particle associated proteins in plasma and cerebrospinal fluid:
RT identification and partial sequencing.";
RL Appl. Theor. Electrophor. 1:73-76(1988).
RN [14]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 34-449 (ISOFORMS 1/2/4), PARTIAL PROTEIN
RP SEQUENCE, SUBUNIT, AND TISSUE SPECIFICITY.
RX PubMed=1974459; DOI=10.1021/bi00474a025;
RA de Silva H.V., Harmony J.A.K., Stuart W.D., Gil C.M., Robbins J.;
RT "Apolipoprotein J: structure and tissue distribution.";
RL Biochemistry 29:5380-5389(1990).
RN [15]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 61-449.
RC TISSUE=Astrocytoma;
RX PubMed=1924317; DOI=10.1073/pnas.88.19.8577;
RA Danik M., Chabot J.G., Mercier C., Benabid A.L., Chauvin C.,
RA Quirion R., Suh M.;
RT "Human gliomas and epileptic foci express high levels of a mRNA
RT related to rat testicular sulfated glycoprotein 2, a purported marker
RT of cell death.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:8577-8581(1991).
RN [16]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 140-449.
RC TISSUE=Fetal liver;
RA Glew M.D., Kirszbaum L., Bozas S.E., Walker I.D.;
RL Submitted (JAN-1993) to the EMBL/GenBank/DDBJ databases.
RN [17]
RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND PARTIAL PROTEIN
RP SEQUENCE.
RC TISSUE=Liver;
RX PubMed=2721499;
RA Kirszbaum L., Sharpe J.A., Murphy B., D'Apice J.F.A., Classon B.,
RA Hudson P., Walker I.D.;
RT "Molecular cloning and characterization of the novel, human
RT complement-associated protein, SP-40,40: a link between the complement
RT and reproductive systems.";
RL EMBO J. 8:711-718(1989).
RN [18]
RP PARTIAL PROTEIN SEQUENCE, DISULFIDE BONDS, AND GLYCOSYLATION AT
RP ASN-86; ASN-103; ASN-145; ASN-291; ASN-354 AND ASN-374.
RX PubMed=1551440; DOI=10.1016/0014-5793(92)80330-J;
RA Kirszbaum L., Bozas S.E., Walker I.D.;
RT "SP-40,40, a protein involved in the control of the complement
RT pathway, possesses a unique array of disulphide bridges.";
RL FEBS Lett. 297:70-76(1992).
RN [19]
RP PARTIAL NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RA Kim J.W.;
RT "Identification of human aging-associated gene.";
RL Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases.
RN [20]
RP INTERACTION WITH APOA1.
RX PubMed=1742316; DOI=10.1016/0005-2760(91)90167-G;
RA Ehnholm C., Bozas S.E., Tenkanen H., Kirszbaum L., Metso J.,
RA Murphy B., Walker I.D.;
RT "The apolipoprotein A-I binding protein of placenta and the SP-40,40
RT protein of human blood are different proteins which both bind to
RT apolipoprotein A-I.";
RL Biochim. Biophys. Acta 1086:255-260(1991).
RN [21]
RP DISULFIDE BONDS.
RX PubMed=1491011;
RA Choi-Miura N.H., Takahashi Y., Nakano Y., Tobe T., Tomita M.;
RT "Identification of the disulfide bonds in human plasma protein SP-
RT 40,40 (apolipoprotein-J).";
RL J. Biochem. 112:557-561(1992).
RN [22]
RP INTERACTION WITH PON1, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=8292612; DOI=10.1021/bi00169a026;
RA Kelso G.J., Stuart W.D., Richter R.J., Furlong C.E.,
RA Jordan-Starck T.C., Harmony J.A.K.;
RT "Apolipoprotein J is associated with paraoxonase in human plasma.";
RL Biochemistry 33:832-839(1994).
RN [23]
RP GLYCOSYLATION AT ASN-86; ASN-103; ASN-145; ASN-291; ASN-354 AND
RP ASN-374.
RC TISSUE=Serum;
RX PubMed=9336835;
RA Kapron J.T., Hilliard G.M., Lakins J.N., Tenniswood M.P., West K.A.,
RA Carr S.A., Crabb J.W.;
RT "Identification and characterization of glycosylation sites in human
RT serum clusterin.";
RL Protein Sci. 6:2120-2133(1997).
RN [24]
RP FUNCTION, SUBCELLULAR LOCATION, ABSENCE OF ATPASE ACTIVITY, AND TISSUE
RP SPECIFICITY.
RX PubMed=11123922; DOI=10.1021/bi002189x;
RA Poon S., Easterbrook-Smith S.B., Rybchyn M.S., Carver J.A.,
RA Wilson M.R.;
RT "Clusterin is an ATP-independent chaperone with very broad substrate
RT specificity that stabilizes stressed proteins in a folding-competent
RT state.";
RL Biochemistry 39:15953-15960(2000).
RN [25]
RP FUNCTION, AND SUBUNIT.
RX PubMed=12047389; DOI=10.1046/j.1432-1033.2002.02957.x;
RA Hatters D.M., Wilson M.R., Easterbrook-Smith S.B., Howlett G.J.;
RT "Suppression of apolipoprotein C-II amyloid formation by the
RT extracellular chaperone, clusterin.";
RL Eur. J. Biochem. 269:2789-2794(2002).
RN [26]
RP FUNCTION, SUBUNIT, AND CIRCULAR DICHROISM.
RX PubMed=12176985; DOI=10.1074/jbc.M204855200;
RA Poon S., Rybchyn M.S., Easterbrook-Smith S.B., Carver J.A.,
RA Pankhurst G.J., Wilson M.R.;
RT "Mildly acidic pH activates the extracellular molecular chaperone
RT clusterin.";
RL J. Biol. Chem. 277:39532-39540(2002).
RN [27]
RP ALTERNATIVE SPLICING, IDENTIFICATION OF ISOFORM 4, FUNCTION,
RP INTERACTION WITH XRCC6, AND SUBCELLULAR LOCATION.
RX PubMed=12551933; DOI=10.1074/jbc.M209233200;
RA Leskov K.S., Klokov D.Y., Li J., Kinsella T.J., Boothman D.A.;
RT "Synthesis and functional analyses of nuclear clusterin, a cell death
RT protein.";
RL J. Biol. Chem. 278:11590-11600(2003).
RN [28]
RP FUNCTION.
RX PubMed=12882985; DOI=10.1074/jbc.C300252200;
RA Santilli G., Aronow B.J., Sala A.;
RT "Essential requirement of apolipoprotein J (clusterin) signaling for
RT IkappaB expression and regulation of NF-kappaB activity.";
RL J. Biol. Chem. 278:38214-38219(2003).
RN [29]
RP GLYCOSYLATION AT ASN-354.
RC TISSUE=Serum;
RX PubMed=12754519; DOI=10.1038/nbt827;
RA Zhang H., Li X.-J., Martin D.B., Aebersold R.;
RT "Identification and quantification of N-linked glycoproteins using
RT hydrazide chemistry, stable isotope labeling and mass spectrometry.";
RL Nat. Biotechnol. 21:660-666(2003).
RN [30]
RP INTERACTION WITH CLUAP1.
RX PubMed=15480429; DOI=10.1038/sj.onc.1208100;
RA Takahashi M., Lin Y.-M., Nakamura Y., Furukawa Y.;
RT "Isolation and characterization of a novel gene CLUAP1 whose
RT expression is frequently upregulated in colon cancer.";
RL Oncogene 23:9289-9294(2004).
RN [31]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-354 AND ASN-374, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=14760718; DOI=10.1002/pmic.200300556;
RA Bunkenborg J., Pilch B.J., Podtelejnikov A.V., Wisniewski J.R.;
RT "Screening for N-glycosylated proteins by liquid chromatography mass
RT spectrometry.";
RL Proteomics 4:454-465(2004).
RN [32]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-86; ASN-103; ASN-145;
RP ASN-291; ASN-354 AND ASN-374, AND MASS SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [33]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH BAX.
RX PubMed=16113678; DOI=10.1038/ncb1291;
RA Zhang H., Kim J.K., Edwards C.A., Xu Z., Taichman R., Wang C.Y.;
RT "Clusterin inhibits apoptosis by interacting with activated Bax.";
RL Nat. Cell Biol. 7:909-915(2005).
RN [34]
RP INDUCTION, AND MASS SPECTROMETRY.
RX PubMed=16548883; DOI=10.1111/j.1462-5822.2005.00644.x;
RA Leong W.F., Chow V.T.;
RT "Transcriptomic and proteomic analyses of rhabdomyosarcoma cells
RT reveal differential cellular gene expression in response to
RT enterovirus 71 infection.";
RL Cell. Microbiol. 8:565-580(2006).
RN [35]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-374, AND MASS
RP SPECTROMETRY.
RC TISSUE=Saliva;
RX PubMed=16740002; DOI=10.1021/pr050492k;
RA Ramachandran P., Boontheung P., Xie Y., Sondej M., Wong D.T.,
RA Loo J.A.;
RT "Identification of N-linked glycoproteins in human saliva by
RT glycoprotein capture and mass spectrometry.";
RL J. Proteome Res. 5:1493-1503(2006).
RN [36]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-374, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=16263699; DOI=10.1074/mcp.M500324-MCP200;
RA Lewandrowski U., Moebius J., Walter U., Sickmann A.;
RT "Elucidation of N-glycosylation sites on human platelet proteins: a
RT glycoproteomic approach.";
RL Mol. Cell. Proteomics 5:226-233(2006).
RN [37]
RP FUNCTION, SUBUNIT, INTERACTION WITH LRP2, GLYCOSYLATION, SUBCELLULAR
RP LOCATION, MASS SPECTROMETRY, CIRCULAR DICHROISM, AND TISSUE
RP SPECIFICITY.
RX PubMed=17260971; DOI=10.1021/bi062082v;
RA Stewart E.M., Aquilina J.A., Easterbrook-Smith S.B.,
RA Murphy-Durland D., Jacobsen C., Moestrup S., Wilson M.R.;
RT "Effects of glycosylation on the structure and function of the
RT extracellular chaperone clusterin.";
RL Biochemistry 46:1412-1422(2007).
RN [38]
RP FUNCTION, INDUCTION, PROTEASOMAL DEGRADATION, AND SUBCELLULAR
RP LOCATION.
RX PubMed=17689225; DOI=10.1016/j.bbadis.2007.06.004;
RA Ranney M.K., Ahmed I.S., Potts K.R., Craven R.J.;
RT "Multiple pathways regulating the anti-apoptotic protein clusterin in
RT breast cancer.";
RL Biochim. Biophys. Acta 1772:1103-1111(2007).
RN [39]
RP IDENTIFICATION IN A COMPLEX WITH LTF; SEMG1 AND EPPIN.
RX PubMed=17567961; DOI=10.1095/biolreprod.107.060194;
RA Wang Z., Widgren E.E., Richardson R.T., O'Rand M.G.;
RT "Characterization of an eppin protein complex from human semen and
RT spermatozoa.";
RL Biol. Reprod. 77:476-484(2007).
RN [40]
RP FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=17412999; DOI=10.1096/fj.06-7986com;
RA Yerbury J.J., Poon S., Meehan S., Thompson B., Kumita J.R.,
RA Dobson C.M., Wilson M.R.;
RT "The extracellular chaperone clusterin influences amyloid formation
RT and toxicity by interacting with prefibrillar structures.";
RL FASEB J. 21:2312-2322(2007).
RN [41]
RP ALTERNATIVE SPLICING, IDENTIFICATION OF ISOFORMS 1 AND 2, AND
RP INDUCTION BY ANDROGEN.
RX PubMed=17148459; DOI=10.1074/jbc.M608162200;
RA Cochrane D.R., Wang Z., Muramaki M., Gleave M.E., Nelson C.C.;
RT "Differential regulation of clusterin and its isoforms by androgens in
RT prostate cells.";
RL J. Biol. Chem. 282:2278-2287(2007).
RN [42]
RP FUNCTION, AND SUBUNIT.
RX PubMed=17407782; DOI=10.1016/j.jmb.2007.02.095;
RA Kumita J.R., Poon S., Caddy G.L., Hagan C.L., Dumoulin M.,
RA Yerbury J.J., Stewart E.M., Robinson C.V., Wilson M.R., Dobson C.M.;
RT "The extracellular chaperone clusterin potently inhibits human
RT lysozyme amyloid formation by interacting with prefibrillar species.";
RL J. Mol. Biol. 369:157-167(2007).
RN [43]
RP ALTERNATIVE SPLICING, IDENTIFICATION OF ISOFORMS 1; 2 AND 5, AND
RP TISSUE SPECIFICITY.
RX PubMed=17322305; DOI=10.1074/mcp.M600261-MCP200;
RA Andersen C.L., Schepeler T., Thorsen K., Birkenkamp-Demtroder K.,
RA Mansilla F., Aaltonen L.A., Laurberg S., Orntoft T.F.;
RT "Clusterin expression in normal mucosa and colorectal cancer.";
RL Mol. Cell. Proteomics 6:1039-1048(2007).
RN [44]
RP SUBCELLULAR LOCATION, INTERACTION WITH SYVN1, AND UBIQUITINATION.
RX PubMed=17451556; DOI=10.1111/j.1600-0854.2007.00549.x;
RA Nizard P., Tetley S., Le Drean Y., Watrin T., Le Goff P., Wilson M.R.,
RA Michel D.;
RT "Stress-induced retrotranslocation of clusterin/ApoJ into the
RT cytosol.";
RL Traffic 8:554-565(2007).
RN [45]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-291; ASN-317 AND ASN-374,
RP AND MASS SPECTROMETRY.
RC TISSUE=Milk;
RX PubMed=18780401; DOI=10.1002/pmic.200701057;
RA Picariello G., Ferranti P., Mamone G., Roepstorff P., Addeo F.;
RT "Identification of N-linked glycoproteins in human milk by hydrophilic
RT interaction liquid chromatography and mass spectrometry.";
RL Proteomics 8:3833-3847(2008).
RN [46]
RP FUNCTION, AND SUBUNIT.
RX PubMed=19535339; DOI=10.1074/jbc.M109.033688;
RA Wyatt A.R., Yerbury J.J., Wilson M.R.;
RT "Structural characterization of clusterin-chaperone client protein
RT complexes.";
RL J. Biol. Chem. 284:21920-21927(2009).
RN [47]
RP FUNCTION, SUBCELLULAR LOCATION, AND UBIQUITINATION.
RX PubMed=19137541; DOI=10.1002/jcp.21671;
RA Rizzi F., Caccamo A.E., Belloni L., Bettuzzi S.;
RT "Clusterin is a short half-life, poly-ubiquitinated protein, which
RT controls the fate of prostate cancer cells.";
RL J. Cell. Physiol. 219:314-323(2009).
RN [48]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-86; ASN-103; ASN-145;
RP ASN-354 AND ASN-374, AND MASS SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [49]
RP GLYCOSYLATION AT ASN-86 AND ASN-374.
RX PubMed=19139490; DOI=10.1074/mcp.M800504-MCP200;
RA Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F.,
RA Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y.,
RA Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.;
RT "A strategy for precise and large scale identification of core
RT fucosylated glycoproteins.";
RL Mol. Cell. Proteomics 8:913-923(2009).
RN [50]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-374, STRUCTURE OF
RP CARBOHYDRATES, AND MASS SPECTROMETRY.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E.,
RA Brinkmalm G., Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [51]
RP FUNCTION.
RX PubMed=19996109; DOI=10.1074/jbc.M109.079566;
RA Wyatt A.R., Wilson M.R.;
RT "Identification of human plasma proteins as major clients for the
RT extracellular chaperone clusterin.";
RL J. Biol. Chem. 285:3532-3539(2010).
RN [52]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH COMMD1; UBIQUITIN;
RP CUL1 ANDBTRC, AND IDENTIFICATION IN A E3 UBIQUITIN-PROTEIN LIGASE
RP COMPLEX.
RX PubMed=20068069; DOI=10.1158/1541-7786.MCR-09-0277;
RA Zoubeidi A., Ettinger S., Beraldi E., Hadaschik B., Zardan A.,
RA Klomp L.W., Nelson C.C., Rennie P.S., Gleave M.E.;
RT "Clusterin facilitates COMMD1 and I-kappaB degradation to enhance NF-
RT kappaB activity in prostate cancer cells.";
RL Mol. Cancer Res. 8:119-130(2010).
RN [53]
RP FUNCTION.
RX PubMed=21505792; DOI=10.1007/s00018-011-0684-8);
RA Wyatt A.R., Yerbury J.J., Berghofer P., Greguric I., Katsifis A.,
RA Dobson C.M., Wilson M.R.;
RT "Clusterin facilitates in vivo clearance of extracellular misfolded
RT proteins.";
RL Cell. Mol. Life Sci. 68:3919-3931(2011).
CC -!- FUNCTION: Isoform 1 functions as extracellular chaperone that
CC prevents aggregation of nonnative proteins. Prevents stress-
CC induced aggregation of blood plasma proteins. Inhibits formation
CC of amyloid fibrils by APP, APOC2, B2M, CALCA, CSN3, SNCA and
CC aggregation-prone LYZ variants (in vitro). Does not require ATP.
CC Maintains partially unfolded proteins in a state appropriate for
CC subsequent refolding by other chaperones, such as HSPA8/HSC70.
CC Does not refold proteins by itself. Binding to cell surface
CC receptors triggers internalization of the chaperone-client complex
CC and subsequent lysosomal or proteasomal degradation. Secreted
CC isoform 1 protects cells against apoptosis and against cytolysis
CC by complement. Intracellular isoforms interact with ubiquitin and
CC SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase
CC complexes and promote the ubiquitination and subsequent
CC proteasomal degradation of target proteins. Promotes proteasomal
CC degradation of COMMD1 and IKBKB. Modulates NF-kappa-B
CC transcriptional activity. Nuclear isoforms promote apoptosis.
CC Mitochondrial isoforms suppress BAX-dependent release of
CC cytochrome c into the cytoplasm and inhibit apoptosis. Plays a
CC role in the regulation of cell proliferation.
CC -!- SUBUNIT: Antiparallel disulfide-linked heterodimer of an alpha
CC chain and a beta chain. Self-associates and forms higher
CC oligomers. Interacts with a broad range of misfolded proteins,
CC including APP, APOC2 and LYZ. Slightly acidic pH promotes
CC interaction with misfolded proteins. Forms high-molecular weight
CC oligomers upon interaction with misfolded proteins. Interacts with
CC APOA1, LRP2, CLUAP1 AND PON1. Interacts with the complement
CC complex. Interacts (via alpha chain) with XRCC6. Interacts with
CC SYVN1, COMMD1, BTRC, CUL1 and with ubiquitin and SCF (SKP1-CUL1-F-
CC box protein) E3 ubiquitin-protein ligase complexes. Interacts (via
CC alpha chain) with BAX in stressed cells, where BAX undergoes a
CC conformation change leading to association with the mitochondrial
CC membrane. Does not interact with BAX in unstressed cells. Found in
CC a complex with LTF, CLU, EPPIN and SEMG1.
CC -!- INTERACTION:
CC Q07817-1:BCL2L1; NbExp=6; IntAct=EBI-4322678, EBI-287195;
CC Q9NRI5:DISC1; NbExp=4; IntAct=EBI-1104674, EBI-529989;
CC P01100:FOS; NbExp=2; IntAct=EBI-1104674, EBI-852851;
CC P37231:PPARG; NbExp=3; IntAct=EBI-1104674, EBI-781384;
CC -!- SUBCELLULAR LOCATION: Isoform 1: Secreted. Note=Can
CC retrotranslocate from the secretory compartments to the cytosol
CC upon cellular stress.
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Mitochondrion membrane;
CC Peripheral membrane protein; Cytoplasmic side. Cytoplasm, cytosol.
CC Microsome. Endoplasmic reticulum. Cytoplasmic vesicle, secretory
CC vesicle, chromaffin granule (By similarity). Note=Isoforms lacking
CC the N-terminal signal sequence have been shown to be cytoplasmic
CC and/or nuclear. Secreted isoforms can retrotranslocate from the
CC secretory compartments to the cytosol upon cellular stress.
CC Detected in perinuclear foci that may be aggresomes containing
CC misfolded, ubiquitinated proteins. Detected at the mitochondrion
CC membrane upon induction of apoptosis.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1; Synonyms=2, CLU35, sCLU;
CC IsoId=P10909-1; Sequence=Displayed;
CC Note=Major isoform;
CC Name=2; Synonyms=1, CLU34;
CC IsoId=P10909-2; Sequence=VSP_037661;
CC Name=3;
CC IsoId=P10909-3; Sequence=VSP_041475;
CC Name=4; Synonyms=nCLU;
CC IsoId=P10909-4; Sequence=VSP_041476;
CC Note=Minor isoform that has been detected in a breast cancer
CC cell line, but not in any other tissues or cell lines;
CC Name=5; Synonyms=CLU36;
CC IsoId=P10909-5; Sequence=VSP_041477;
CC -!- TISSUE SPECIFICITY: Detected in blood plasma, cerebrospinal fluid,
CC milk, seminal plasma and colon mucosa. Detected in the germinal
CC center of colon lymphoid nodules and in colon parasympathetic
CC ganglia of the Auerbach plexus (at protein level). Ubiquitous.
CC Detected in brain, testis, ovary, liver and pancreas, and at lower
CC levels in kidney, heart, spleen and lung.
CC -!- INDUCTION: Up-regulated in response to enterovirus 71 (EV71)
CC infection (at protein level). Up-regulated by agents that induce
CC apoptosis, both at mRNA and protein level. Isoform 1 is up-
CC regulated by androgen. Isoform 2 is down-regulated by androgen.
CC -!- PTM: Isoform 1 is proteolytically cleaved on its way through the
CC secretory system, probably within the Golgi lumen.
CC -!- PTM: Polyubiquitinated, leading to proteasomal degradation.
CC -!- PTM: Heavily N-glycosylated. About 30% of the protein mass is
CC comprised of complex N-linked carbohydrate.
CC -!- SIMILARITY: Belongs to the clusterin family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA35692.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAB06508.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAB06508.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence;
CC Sequence=AAH10514.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAH19588.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAP88927.1; Type=Erroneous gene model prediction;
CC Sequence=AAP88927.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAT08041.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=BAG36598.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=CAA32847.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/clu/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/CLUID40107ch8p21.html";
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DR EMBL; M25915; AAA35692.1; ALT_INIT; mRNA.
DR EMBL; M63379; AAB06507.1; -; Genomic_DNA.
DR EMBL; M63376; AAB06507.1; JOINED; Genomic_DNA.
DR EMBL; M63377; AAB06507.1; JOINED; Genomic_DNA.
DR EMBL; M63378; AAB06507.1; JOINED; Genomic_DNA.
DR EMBL; M64722; AAB06508.1; ALT_SEQ; mRNA.
DR EMBL; AK093399; BAG52708.1; -; mRNA.
DR EMBL; AK313870; BAG36598.1; ALT_INIT; mRNA.
DR EMBL; CR599675; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BX648414; CAI45990.1; -; mRNA.
DR EMBL; AY341244; AAP88927.1; ALT_INIT; Genomic_DNA.
DR EMBL; AF311103; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC010514; AAH10514.1; ALT_INIT; mRNA.
DR EMBL; BC019588; AAH19588.1; ALT_INIT; mRNA.
DR EMBL; BU150467; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; J02908; AAA51765.1; -; mRNA.
DR EMBL; M74816; AAA60321.1; -; mRNA.
DR EMBL; L00974; AAA60567.1; -; Genomic_DNA.
DR EMBL; X14723; CAA32847.1; ALT_INIT; mRNA.
DR EMBL; AY513288; AAT08041.1; ALT_INIT; mRNA.
DR PIR; S43646; A41386.
DR RefSeq; NP_001822.3; NM_001831.3.
DR UniGene; Hs.436657; -.
DR ProteinModelPortal; P10909; -.
DR IntAct; P10909; 28.
DR MINT; MINT-3007494; -.
DR STRING; 9606.ENSP00000315130; -.
DR PhosphoSite; P10909; -.
DR DMDM; 116533; -.
DR DOSAC-COBS-2DPAGE; P10909; -.
DR OGP; P10909; -.
DR REPRODUCTION-2DPAGE; IPI00291262; -.
DR SWISS-2DPAGE; P10909; -.
DR PaxDb; P10909; -.
DR PRIDE; P10909; -.
DR DNASU; 1191; -.
DR Ensembl; ENST00000316403; ENSP00000315130; ENSG00000120885.
DR Ensembl; ENST00000405140; ENSP00000385419; ENSG00000120885.
DR Ensembl; ENST00000523500; ENSP00000429620; ENSG00000120885.
DR Ensembl; ENST00000546343; ENSP00000446413; ENSG00000120885.
DR Ensembl; ENST00000560366; ENSP00000453939; ENSG00000120885.
DR GeneID; 1191; -.
DR KEGG; hsa:1191; -.
DR UCSC; uc003xfw.2; human.
DR CTD; 1191; -.
DR GeneCards; GC08M027454; -.
DR HGNC; HGNC:2095; CLU.
DR HPA; CAB000476; -.
DR HPA; CAB016253; -.
DR HPA; HPA000572; -.
DR MIM; 185430; gene.
DR neXtProt; NX_P10909; -.
DR PharmGKB; PA26620; -.
DR eggNOG; NOG26650; -.
DR HOVERGEN; HBG006908; -.
DR InParanoid; P10909; -.
DR KO; K17252; -.
DR OMA; KFYARVC; -.
DR OrthoDB; EOG7K6PV4; -.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; CLU; human.
DR GeneWiki; Clusterin; -.
DR GenomeRNAi; 1191; -.
DR NextBio; 4922; -.
DR PMAP-CutDB; P10909; -.
DR PRO; PR:P10909; -.
DR ArrayExpress; P10909; -.
DR Bgee; P10909; -.
DR CleanEx; HS_CLU; -.
DR Genevestigator; P10909; -.
DR GO; GO:0042583; C:chromaffin granule; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0031966; C:mitochondrial membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:BHF-UCL.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0034366; C:spherical high-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0051787; F:misfolded protein binding; IDA:UniProtKB.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IDA:UniProtKB.
DR GO; GO:0061077; P:chaperone-mediated protein folding; IDA:UniProtKB.
DR GO; GO:0006956; P:complement activation; TAS:ProtInc.
DR GO; GO:0006958; P:complement activation, classical pathway; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:0006629; P:lipid metabolic process; NAS:ProtInc.
DR GO; GO:1902230; P:negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage; IMP:BHF-UCL.
DR GO; GO:0032463; P:negative regulation of protein homooligomerization; IMP:BHF-UCL.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IMP:UniProtKB.
DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:2000060; P:positive regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; IDA:UniProtKB.
DR GO; GO:0001836; P:release of cytochrome c from mitochondria; IC:BHF-UCL.
DR GO; GO:0051788; P:response to misfolded protein; IDA:BHF-UCL.
DR GO; GO:0009615; P:response to virus; IEP:UniProtKB.
DR GO; GO:0043691; P:reverse cholesterol transport; TAS:BHF-UCL.
DR InterPro; IPR016016; Clusterin.
DR InterPro; IPR000753; Clusterin-like.
DR InterPro; IPR016015; Clusterin_C.
DR InterPro; IPR016014; Clusterin_N.
DR PANTHER; PTHR10970:SF1; PTHR10970:SF1; 1.
DR Pfam; PF01093; Clusterin; 1.
DR PIRSF; PIRSF002368; Clusterin; 1.
DR SMART; SM00035; CLa; 1.
DR SMART; SM00030; CLb; 1.
DR PROSITE; PS00492; CLUSTERIN_1; 1.
DR PROSITE; PS00493; CLUSTERIN_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Apoptosis; Chaperone; Complement pathway;
KW Complete proteome; Cytoplasm; Cytoplasmic vesicle;
KW Direct protein sequencing; Disulfide bond; Endoplasmic reticulum;
KW Glycoprotein; Immunity; Innate immunity; Membrane; Microsome;
KW Mitochondrion; Nucleus; Polymorphism; Reference proteome; Secreted;
KW Signal; Ubl conjugation.
FT SIGNAL 1 22
FT CHAIN 23 449 Clusterin.
FT /FTId=PRO_0000005529.
FT CHAIN 23 227 Clusterin beta chain.
FT /FTId=PRO_0000005530.
FT CHAIN 228 449 Clusterin alpha chain.
FT /FTId=PRO_0000005531.
FT MOTIF 78 81 Nuclear localization signal (By
FT similarity).
FT MOTIF 443 447 Nuclear localization signal (By
FT similarity).
FT CARBOHYD 86 86 N-linked (GlcNAc...) (complex).
FT CARBOHYD 103 103 N-linked (GlcNAc...).
FT CARBOHYD 145 145 N-linked (GlcNAc...).
FT CARBOHYD 291 291 N-linked (GlcNAc...).
FT CARBOHYD 317 317 N-linked (GlcNAc...).
FT CARBOHYD 354 354 N-linked (GlcNAc...).
FT CARBOHYD 374 374 N-linked (GlcNAc...) (complex).
FT DISULFID 102 313 Interchain (between beta and alpha
FT chains).
FT DISULFID 113 305 Interchain (between beta and alpha
FT chains).
FT DISULFID 116 302 Interchain (between beta and alpha
FT chains).
FT DISULFID 121 295 Interchain (between beta and alpha
FT chains).
FT DISULFID 129 285 Interchain (between beta and alpha
FT chains).
FT VAR_SEQ 1 175 Missing (in isoform 3).
FT /FTId=VSP_041475.
FT VAR_SEQ 1 33 Missing (in isoform 4).
FT /FTId=VSP_041476.
FT VAR_SEQ 1 1 M -> MQVCSQPQRGCVREQSAINTAPPSAHNAASPGGARG
FT HRVPLTEACKDSRIGGM (in isoform 2).
FT /FTId=VSP_037661.
FT VAR_SEQ 1 1 M -> MEACKDSRIGGM (in isoform 5).
FT /FTId=VSP_041477.
FT VARIANT 317 317 N -> H (in dbSNP:rs9331936).
FT /FTId=VAR_019366.
FT VARIANT 328 328 D -> N (in dbSNP:rs9331938).
FT /FTId=VAR_019367.
FT VARIANT 396 396 S -> L (in dbSNP:rs13494).
FT /FTId=VAR_019368.
FT CONFLICT 28 28 D -> S (in Ref. 9; AA sequence and 13; AA
FT sequence).
FT CONFLICT 47 47 Q -> H (in Ref. 10; AA sequence).
FT CONFLICT 52 52 G -> Q (in Ref. 10; AA sequence).
FT CONFLICT 172 172 M -> V (in Ref. 5; CAI45990).
FT CONFLICT 224 224 R -> L (in Ref. 3; BAG36598).
FT CONFLICT 305 305 C -> M (in Ref. 9; AA sequence).
FT CONFLICT 388 388 T -> M (in Ref. 5; CAI45990).
FT CONFLICT 411 411 D -> G (in Ref. 3; BAG36598).
SQ SEQUENCE 449 AA; 52495 MW; 9583DE4CCECC169F CRC64;
MMKTLLLFVG LLLTWESGQV LGDQTVSDNE LQEMSNQGSK YVNKEIQNAV NGVKQIKTLI
EKTNEERKTL LSNLEEAKKK KEDALNETRE SETKLKELPG VCNETMMALW EECKPCLKQT
CMKFYARVCR SGSGLVGRQL EEFLNQSSPF YFWMNGDRID SLLENDRQQT HMLDVMQDHF
SRASSIIDEL FQDRFFTREP QDTYHYLPFS LPHRRPHFFF PKSRIVRSLM PFSPYEPLNF
HAMFQPFLEM IHEAQQAMDI HFHSPAFQHP PTEFIREGDD DRTVCREIRH NSTGCLRMKD
QCDKCREILS VDCSTNNPSQ AKLRRELDES LQVAERLTRK YNELLKSYQW KMLNTSSLLE
QLNEQFNWVS RLANLTQGED QYYLRVTTVA SHTSDSDVPS GVTEVVVKLF DSDPITVTVP
VEVSRKNPKF METVAEKALQ EYRKKHREE
//
ID CLUS_HUMAN Reviewed; 449 AA.
AC P10909; B2R9Q1; B3KSE6; P11380; P11381; Q2TU75; Q5HYC1; Q7Z5B9;
read moreDT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1989, sequence version 1.
DT 22-JAN-2014, entry version 164.
DE RecName: Full=Clusterin;
DE AltName: Full=Aging-associated gene 4 protein;
DE AltName: Full=Apolipoprotein J;
DE Short=Apo-J;
DE AltName: Full=Complement cytolysis inhibitor;
DE Short=CLI;
DE AltName: Full=Complement-associated protein SP-40,40;
DE AltName: Full=Ku70-binding protein 1;
DE AltName: Full=NA1/NA2;
DE AltName: Full=Testosterone-repressed prostate message 2;
DE Short=TRPM-2;
DE Contains:
DE RecName: Full=Clusterin beta chain;
DE AltName: Full=ApoJalpha;
DE AltName: Full=Complement cytolysis inhibitor a chain;
DE Contains:
DE RecName: Full=Clusterin alpha chain;
DE AltName: Full=ApoJbeta;
DE AltName: Full=Complement cytolysis inhibitor b chain;
DE Flags: Precursor;
GN Name=CLU; Synonyms=APOJ, CLI, KUB1; ORFNames=AAG4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF
RP N-TERMINUS, SUBUNIT, DISULFIDE BONDS, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Liver;
RX PubMed=2780565; DOI=10.1073/pnas.86.18.7123;
RA Jenne D.E., Tschopp J.;
RT "Molecular structure and functional characterization of a human
RT complement cytolysis inhibitor found in blood and seminal plasma:
RT identity to sulfated glycoprotein 2, a constituent of rat testis
RT fluid.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:7123-7127(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], PARTIAL NUCLEOTIDE SEQUENCE [MRNA]
RP (ISOFORM 2), AND TISSUE SPECIFICITY.
RX PubMed=8181474; DOI=10.1111/j.1432-1033.1994.tb18807.x;
RA Wong P., Taillefer D., Lakins J., Pineault J., Chader G.,
RA Tenniswood M.;
RT "Molecular characterization of human TRPM-2/clusterin, a gene
RT associated with sperm maturation, apoptosis and neurodegeneration.";
RL Eur. J. Biochem. 221:917-925(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3), AND PARTIAL
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Stomach, and Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RA Li W.B., Gruber C., Jessee J., Polayes D.;
RT "Full-length cDNA libraries and normalization.";
RL Submitted (JUL-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Small intestine;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS HIS-317; ASN-328 AND
RP LEU-396.
RG NIEHS SNPs program;
RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S.,
RA Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A.,
RA Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X.,
RA Allen N.R., Anderson S., Asakawa T., Blechschmidt K., Bloom T.,
RA Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K.,
RA DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G.,
RA Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B.,
RA Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C.,
RA O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K.,
RA Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R.,
RA Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K.,
RA Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q.,
RA Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N.,
RA Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5), AND PARTIAL
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain, and Spinal ganglion;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP PROTEIN SEQUENCE OF 23-33; 229-242; 303-317 AND 397-403, SUBUNIT, AND
RP INTERACTION WITH APOA1.
RX PubMed=1903064;
RA James R.W., Hochstrasser A.-C., Borghini I., Martin B.M., Pometta D.,
RA Hochstrasser D.F.;
RT "Characterization of a human high density lipoprotein-associated
RT protein, NA1/NA2. Identity with SP-40,40, an inhibitor of complement-
RT mediated cytolysis.";
RL Arterioscler. Thromb. 11:645-652(1991).
RN [10]
RP PROTEIN SEQUENCE OF 23-52 AND 228-257, SUBUNIT, DISULFIDE BOND,
RP PROTEOLYTIC PROCESSING, GLYCOSYLATION, SUBCELLULAR LOCATION, AND
RP TISSUE SPECIFICITY.
RX PubMed=2387851;
RA de Silva H., Stuart W.D., Park Y.B., Mao S.J.T., Gil C.M.,
RA Wetterau J.R., Busch S.J., Harmony J.A.K.;
RT "Purification and characterization of apolipoprotein J.";
RL J. Biol. Chem. 265:14292-14297(1990).
RN [11]
RP PROTEIN SEQUENCE OF 23-41 AND 228-246, INTERACTION WITH APP,
RP SUBCELLULAR LOCATION, DISULFIDE BOND, AND TISSUE SPECIFICITY.
RX PubMed=8328966;
RA Ghiso J., Matsubara E., Koudinov A., Choi-Miura N.-H., Tomita M.,
RA Wisniewski T., Frangione B.;
RT "The cerebrospinal-fluid soluble form of Alzheimer's amyloid beta is
RT complexed to SP-40,40 (apolipoprotein J), an inhibitor of the
RT complement membrane-attack complex.";
RL Biochem. J. 293:27-30(1993).
RN [12]
RP PROTEIN SEQUENCE OF 23-37 AND 228-242.
RX PubMed=2601725; DOI=10.1016/0161-5890(89)90139-9;
RA Choi N.H., Mazda T., Tomita M.;
RT "A serum protein SP40,40 modulates the formation of membrane attack
RT complex of complement on erythrocytes.";
RL Mol. Immunol. 26:835-840(1989).
RN [13]
RP PROTEIN SEQUENCE OF 23-33 AND 228-240, SUBCELLULAR LOCATION, AND
RP TISSUE SPECIFICITY.
RX PubMed=3154963;
RA Hochstrasser A.-C., James R.W., Martin B.M., Harrington M.,
RA Hochstrasser D.F., Pometta D., Merril C.R.;
RT "HDL particle associated proteins in plasma and cerebrospinal fluid:
RT identification and partial sequencing.";
RL Appl. Theor. Electrophor. 1:73-76(1988).
RN [14]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 34-449 (ISOFORMS 1/2/4), PARTIAL PROTEIN
RP SEQUENCE, SUBUNIT, AND TISSUE SPECIFICITY.
RX PubMed=1974459; DOI=10.1021/bi00474a025;
RA de Silva H.V., Harmony J.A.K., Stuart W.D., Gil C.M., Robbins J.;
RT "Apolipoprotein J: structure and tissue distribution.";
RL Biochemistry 29:5380-5389(1990).
RN [15]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 61-449.
RC TISSUE=Astrocytoma;
RX PubMed=1924317; DOI=10.1073/pnas.88.19.8577;
RA Danik M., Chabot J.G., Mercier C., Benabid A.L., Chauvin C.,
RA Quirion R., Suh M.;
RT "Human gliomas and epileptic foci express high levels of a mRNA
RT related to rat testicular sulfated glycoprotein 2, a purported marker
RT of cell death.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:8577-8581(1991).
RN [16]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 140-449.
RC TISSUE=Fetal liver;
RA Glew M.D., Kirszbaum L., Bozas S.E., Walker I.D.;
RL Submitted (JAN-1993) to the EMBL/GenBank/DDBJ databases.
RN [17]
RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND PARTIAL PROTEIN
RP SEQUENCE.
RC TISSUE=Liver;
RX PubMed=2721499;
RA Kirszbaum L., Sharpe J.A., Murphy B., D'Apice J.F.A., Classon B.,
RA Hudson P., Walker I.D.;
RT "Molecular cloning and characterization of the novel, human
RT complement-associated protein, SP-40,40: a link between the complement
RT and reproductive systems.";
RL EMBO J. 8:711-718(1989).
RN [18]
RP PARTIAL PROTEIN SEQUENCE, DISULFIDE BONDS, AND GLYCOSYLATION AT
RP ASN-86; ASN-103; ASN-145; ASN-291; ASN-354 AND ASN-374.
RX PubMed=1551440; DOI=10.1016/0014-5793(92)80330-J;
RA Kirszbaum L., Bozas S.E., Walker I.D.;
RT "SP-40,40, a protein involved in the control of the complement
RT pathway, possesses a unique array of disulphide bridges.";
RL FEBS Lett. 297:70-76(1992).
RN [19]
RP PARTIAL NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RA Kim J.W.;
RT "Identification of human aging-associated gene.";
RL Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases.
RN [20]
RP INTERACTION WITH APOA1.
RX PubMed=1742316; DOI=10.1016/0005-2760(91)90167-G;
RA Ehnholm C., Bozas S.E., Tenkanen H., Kirszbaum L., Metso J.,
RA Murphy B., Walker I.D.;
RT "The apolipoprotein A-I binding protein of placenta and the SP-40,40
RT protein of human blood are different proteins which both bind to
RT apolipoprotein A-I.";
RL Biochim. Biophys. Acta 1086:255-260(1991).
RN [21]
RP DISULFIDE BONDS.
RX PubMed=1491011;
RA Choi-Miura N.H., Takahashi Y., Nakano Y., Tobe T., Tomita M.;
RT "Identification of the disulfide bonds in human plasma protein SP-
RT 40,40 (apolipoprotein-J).";
RL J. Biochem. 112:557-561(1992).
RN [22]
RP INTERACTION WITH PON1, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=8292612; DOI=10.1021/bi00169a026;
RA Kelso G.J., Stuart W.D., Richter R.J., Furlong C.E.,
RA Jordan-Starck T.C., Harmony J.A.K.;
RT "Apolipoprotein J is associated with paraoxonase in human plasma.";
RL Biochemistry 33:832-839(1994).
RN [23]
RP GLYCOSYLATION AT ASN-86; ASN-103; ASN-145; ASN-291; ASN-354 AND
RP ASN-374.
RC TISSUE=Serum;
RX PubMed=9336835;
RA Kapron J.T., Hilliard G.M., Lakins J.N., Tenniswood M.P., West K.A.,
RA Carr S.A., Crabb J.W.;
RT "Identification and characterization of glycosylation sites in human
RT serum clusterin.";
RL Protein Sci. 6:2120-2133(1997).
RN [24]
RP FUNCTION, SUBCELLULAR LOCATION, ABSENCE OF ATPASE ACTIVITY, AND TISSUE
RP SPECIFICITY.
RX PubMed=11123922; DOI=10.1021/bi002189x;
RA Poon S., Easterbrook-Smith S.B., Rybchyn M.S., Carver J.A.,
RA Wilson M.R.;
RT "Clusterin is an ATP-independent chaperone with very broad substrate
RT specificity that stabilizes stressed proteins in a folding-competent
RT state.";
RL Biochemistry 39:15953-15960(2000).
RN [25]
RP FUNCTION, AND SUBUNIT.
RX PubMed=12047389; DOI=10.1046/j.1432-1033.2002.02957.x;
RA Hatters D.M., Wilson M.R., Easterbrook-Smith S.B., Howlett G.J.;
RT "Suppression of apolipoprotein C-II amyloid formation by the
RT extracellular chaperone, clusterin.";
RL Eur. J. Biochem. 269:2789-2794(2002).
RN [26]
RP FUNCTION, SUBUNIT, AND CIRCULAR DICHROISM.
RX PubMed=12176985; DOI=10.1074/jbc.M204855200;
RA Poon S., Rybchyn M.S., Easterbrook-Smith S.B., Carver J.A.,
RA Pankhurst G.J., Wilson M.R.;
RT "Mildly acidic pH activates the extracellular molecular chaperone
RT clusterin.";
RL J. Biol. Chem. 277:39532-39540(2002).
RN [27]
RP ALTERNATIVE SPLICING, IDENTIFICATION OF ISOFORM 4, FUNCTION,
RP INTERACTION WITH XRCC6, AND SUBCELLULAR LOCATION.
RX PubMed=12551933; DOI=10.1074/jbc.M209233200;
RA Leskov K.S., Klokov D.Y., Li J., Kinsella T.J., Boothman D.A.;
RT "Synthesis and functional analyses of nuclear clusterin, a cell death
RT protein.";
RL J. Biol. Chem. 278:11590-11600(2003).
RN [28]
RP FUNCTION.
RX PubMed=12882985; DOI=10.1074/jbc.C300252200;
RA Santilli G., Aronow B.J., Sala A.;
RT "Essential requirement of apolipoprotein J (clusterin) signaling for
RT IkappaB expression and regulation of NF-kappaB activity.";
RL J. Biol. Chem. 278:38214-38219(2003).
RN [29]
RP GLYCOSYLATION AT ASN-354.
RC TISSUE=Serum;
RX PubMed=12754519; DOI=10.1038/nbt827;
RA Zhang H., Li X.-J., Martin D.B., Aebersold R.;
RT "Identification and quantification of N-linked glycoproteins using
RT hydrazide chemistry, stable isotope labeling and mass spectrometry.";
RL Nat. Biotechnol. 21:660-666(2003).
RN [30]
RP INTERACTION WITH CLUAP1.
RX PubMed=15480429; DOI=10.1038/sj.onc.1208100;
RA Takahashi M., Lin Y.-M., Nakamura Y., Furukawa Y.;
RT "Isolation and characterization of a novel gene CLUAP1 whose
RT expression is frequently upregulated in colon cancer.";
RL Oncogene 23:9289-9294(2004).
RN [31]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-354 AND ASN-374, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=14760718; DOI=10.1002/pmic.200300556;
RA Bunkenborg J., Pilch B.J., Podtelejnikov A.V., Wisniewski J.R.;
RT "Screening for N-glycosylated proteins by liquid chromatography mass
RT spectrometry.";
RL Proteomics 4:454-465(2004).
RN [32]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-86; ASN-103; ASN-145;
RP ASN-291; ASN-354 AND ASN-374, AND MASS SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [33]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH BAX.
RX PubMed=16113678; DOI=10.1038/ncb1291;
RA Zhang H., Kim J.K., Edwards C.A., Xu Z., Taichman R., Wang C.Y.;
RT "Clusterin inhibits apoptosis by interacting with activated Bax.";
RL Nat. Cell Biol. 7:909-915(2005).
RN [34]
RP INDUCTION, AND MASS SPECTROMETRY.
RX PubMed=16548883; DOI=10.1111/j.1462-5822.2005.00644.x;
RA Leong W.F., Chow V.T.;
RT "Transcriptomic and proteomic analyses of rhabdomyosarcoma cells
RT reveal differential cellular gene expression in response to
RT enterovirus 71 infection.";
RL Cell. Microbiol. 8:565-580(2006).
RN [35]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-374, AND MASS
RP SPECTROMETRY.
RC TISSUE=Saliva;
RX PubMed=16740002; DOI=10.1021/pr050492k;
RA Ramachandran P., Boontheung P., Xie Y., Sondej M., Wong D.T.,
RA Loo J.A.;
RT "Identification of N-linked glycoproteins in human saliva by
RT glycoprotein capture and mass spectrometry.";
RL J. Proteome Res. 5:1493-1503(2006).
RN [36]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-374, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=16263699; DOI=10.1074/mcp.M500324-MCP200;
RA Lewandrowski U., Moebius J., Walter U., Sickmann A.;
RT "Elucidation of N-glycosylation sites on human platelet proteins: a
RT glycoproteomic approach.";
RL Mol. Cell. Proteomics 5:226-233(2006).
RN [37]
RP FUNCTION, SUBUNIT, INTERACTION WITH LRP2, GLYCOSYLATION, SUBCELLULAR
RP LOCATION, MASS SPECTROMETRY, CIRCULAR DICHROISM, AND TISSUE
RP SPECIFICITY.
RX PubMed=17260971; DOI=10.1021/bi062082v;
RA Stewart E.M., Aquilina J.A., Easterbrook-Smith S.B.,
RA Murphy-Durland D., Jacobsen C., Moestrup S., Wilson M.R.;
RT "Effects of glycosylation on the structure and function of the
RT extracellular chaperone clusterin.";
RL Biochemistry 46:1412-1422(2007).
RN [38]
RP FUNCTION, INDUCTION, PROTEASOMAL DEGRADATION, AND SUBCELLULAR
RP LOCATION.
RX PubMed=17689225; DOI=10.1016/j.bbadis.2007.06.004;
RA Ranney M.K., Ahmed I.S., Potts K.R., Craven R.J.;
RT "Multiple pathways regulating the anti-apoptotic protein clusterin in
RT breast cancer.";
RL Biochim. Biophys. Acta 1772:1103-1111(2007).
RN [39]
RP IDENTIFICATION IN A COMPLEX WITH LTF; SEMG1 AND EPPIN.
RX PubMed=17567961; DOI=10.1095/biolreprod.107.060194;
RA Wang Z., Widgren E.E., Richardson R.T., O'Rand M.G.;
RT "Characterization of an eppin protein complex from human semen and
RT spermatozoa.";
RL Biol. Reprod. 77:476-484(2007).
RN [40]
RP FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=17412999; DOI=10.1096/fj.06-7986com;
RA Yerbury J.J., Poon S., Meehan S., Thompson B., Kumita J.R.,
RA Dobson C.M., Wilson M.R.;
RT "The extracellular chaperone clusterin influences amyloid formation
RT and toxicity by interacting with prefibrillar structures.";
RL FASEB J. 21:2312-2322(2007).
RN [41]
RP ALTERNATIVE SPLICING, IDENTIFICATION OF ISOFORMS 1 AND 2, AND
RP INDUCTION BY ANDROGEN.
RX PubMed=17148459; DOI=10.1074/jbc.M608162200;
RA Cochrane D.R., Wang Z., Muramaki M., Gleave M.E., Nelson C.C.;
RT "Differential regulation of clusterin and its isoforms by androgens in
RT prostate cells.";
RL J. Biol. Chem. 282:2278-2287(2007).
RN [42]
RP FUNCTION, AND SUBUNIT.
RX PubMed=17407782; DOI=10.1016/j.jmb.2007.02.095;
RA Kumita J.R., Poon S., Caddy G.L., Hagan C.L., Dumoulin M.,
RA Yerbury J.J., Stewart E.M., Robinson C.V., Wilson M.R., Dobson C.M.;
RT "The extracellular chaperone clusterin potently inhibits human
RT lysozyme amyloid formation by interacting with prefibrillar species.";
RL J. Mol. Biol. 369:157-167(2007).
RN [43]
RP ALTERNATIVE SPLICING, IDENTIFICATION OF ISOFORMS 1; 2 AND 5, AND
RP TISSUE SPECIFICITY.
RX PubMed=17322305; DOI=10.1074/mcp.M600261-MCP200;
RA Andersen C.L., Schepeler T., Thorsen K., Birkenkamp-Demtroder K.,
RA Mansilla F., Aaltonen L.A., Laurberg S., Orntoft T.F.;
RT "Clusterin expression in normal mucosa and colorectal cancer.";
RL Mol. Cell. Proteomics 6:1039-1048(2007).
RN [44]
RP SUBCELLULAR LOCATION, INTERACTION WITH SYVN1, AND UBIQUITINATION.
RX PubMed=17451556; DOI=10.1111/j.1600-0854.2007.00549.x;
RA Nizard P., Tetley S., Le Drean Y., Watrin T., Le Goff P., Wilson M.R.,
RA Michel D.;
RT "Stress-induced retrotranslocation of clusterin/ApoJ into the
RT cytosol.";
RL Traffic 8:554-565(2007).
RN [45]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-291; ASN-317 AND ASN-374,
RP AND MASS SPECTROMETRY.
RC TISSUE=Milk;
RX PubMed=18780401; DOI=10.1002/pmic.200701057;
RA Picariello G., Ferranti P., Mamone G., Roepstorff P., Addeo F.;
RT "Identification of N-linked glycoproteins in human milk by hydrophilic
RT interaction liquid chromatography and mass spectrometry.";
RL Proteomics 8:3833-3847(2008).
RN [46]
RP FUNCTION, AND SUBUNIT.
RX PubMed=19535339; DOI=10.1074/jbc.M109.033688;
RA Wyatt A.R., Yerbury J.J., Wilson M.R.;
RT "Structural characterization of clusterin-chaperone client protein
RT complexes.";
RL J. Biol. Chem. 284:21920-21927(2009).
RN [47]
RP FUNCTION, SUBCELLULAR LOCATION, AND UBIQUITINATION.
RX PubMed=19137541; DOI=10.1002/jcp.21671;
RA Rizzi F., Caccamo A.E., Belloni L., Bettuzzi S.;
RT "Clusterin is a short half-life, poly-ubiquitinated protein, which
RT controls the fate of prostate cancer cells.";
RL J. Cell. Physiol. 219:314-323(2009).
RN [48]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-86; ASN-103; ASN-145;
RP ASN-354 AND ASN-374, AND MASS SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [49]
RP GLYCOSYLATION AT ASN-86 AND ASN-374.
RX PubMed=19139490; DOI=10.1074/mcp.M800504-MCP200;
RA Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F.,
RA Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y.,
RA Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.;
RT "A strategy for precise and large scale identification of core
RT fucosylated glycoproteins.";
RL Mol. Cell. Proteomics 8:913-923(2009).
RN [50]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-374, STRUCTURE OF
RP CARBOHYDRATES, AND MASS SPECTROMETRY.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E.,
RA Brinkmalm G., Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [51]
RP FUNCTION.
RX PubMed=19996109; DOI=10.1074/jbc.M109.079566;
RA Wyatt A.R., Wilson M.R.;
RT "Identification of human plasma proteins as major clients for the
RT extracellular chaperone clusterin.";
RL J. Biol. Chem. 285:3532-3539(2010).
RN [52]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH COMMD1; UBIQUITIN;
RP CUL1 ANDBTRC, AND IDENTIFICATION IN A E3 UBIQUITIN-PROTEIN LIGASE
RP COMPLEX.
RX PubMed=20068069; DOI=10.1158/1541-7786.MCR-09-0277;
RA Zoubeidi A., Ettinger S., Beraldi E., Hadaschik B., Zardan A.,
RA Klomp L.W., Nelson C.C., Rennie P.S., Gleave M.E.;
RT "Clusterin facilitates COMMD1 and I-kappaB degradation to enhance NF-
RT kappaB activity in prostate cancer cells.";
RL Mol. Cancer Res. 8:119-130(2010).
RN [53]
RP FUNCTION.
RX PubMed=21505792; DOI=10.1007/s00018-011-0684-8);
RA Wyatt A.R., Yerbury J.J., Berghofer P., Greguric I., Katsifis A.,
RA Dobson C.M., Wilson M.R.;
RT "Clusterin facilitates in vivo clearance of extracellular misfolded
RT proteins.";
RL Cell. Mol. Life Sci. 68:3919-3931(2011).
CC -!- FUNCTION: Isoform 1 functions as extracellular chaperone that
CC prevents aggregation of nonnative proteins. Prevents stress-
CC induced aggregation of blood plasma proteins. Inhibits formation
CC of amyloid fibrils by APP, APOC2, B2M, CALCA, CSN3, SNCA and
CC aggregation-prone LYZ variants (in vitro). Does not require ATP.
CC Maintains partially unfolded proteins in a state appropriate for
CC subsequent refolding by other chaperones, such as HSPA8/HSC70.
CC Does not refold proteins by itself. Binding to cell surface
CC receptors triggers internalization of the chaperone-client complex
CC and subsequent lysosomal or proteasomal degradation. Secreted
CC isoform 1 protects cells against apoptosis and against cytolysis
CC by complement. Intracellular isoforms interact with ubiquitin and
CC SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase
CC complexes and promote the ubiquitination and subsequent
CC proteasomal degradation of target proteins. Promotes proteasomal
CC degradation of COMMD1 and IKBKB. Modulates NF-kappa-B
CC transcriptional activity. Nuclear isoforms promote apoptosis.
CC Mitochondrial isoforms suppress BAX-dependent release of
CC cytochrome c into the cytoplasm and inhibit apoptosis. Plays a
CC role in the regulation of cell proliferation.
CC -!- SUBUNIT: Antiparallel disulfide-linked heterodimer of an alpha
CC chain and a beta chain. Self-associates and forms higher
CC oligomers. Interacts with a broad range of misfolded proteins,
CC including APP, APOC2 and LYZ. Slightly acidic pH promotes
CC interaction with misfolded proteins. Forms high-molecular weight
CC oligomers upon interaction with misfolded proteins. Interacts with
CC APOA1, LRP2, CLUAP1 AND PON1. Interacts with the complement
CC complex. Interacts (via alpha chain) with XRCC6. Interacts with
CC SYVN1, COMMD1, BTRC, CUL1 and with ubiquitin and SCF (SKP1-CUL1-F-
CC box protein) E3 ubiquitin-protein ligase complexes. Interacts (via
CC alpha chain) with BAX in stressed cells, where BAX undergoes a
CC conformation change leading to association with the mitochondrial
CC membrane. Does not interact with BAX in unstressed cells. Found in
CC a complex with LTF, CLU, EPPIN and SEMG1.
CC -!- INTERACTION:
CC Q07817-1:BCL2L1; NbExp=6; IntAct=EBI-4322678, EBI-287195;
CC Q9NRI5:DISC1; NbExp=4; IntAct=EBI-1104674, EBI-529989;
CC P01100:FOS; NbExp=2; IntAct=EBI-1104674, EBI-852851;
CC P37231:PPARG; NbExp=3; IntAct=EBI-1104674, EBI-781384;
CC -!- SUBCELLULAR LOCATION: Isoform 1: Secreted. Note=Can
CC retrotranslocate from the secretory compartments to the cytosol
CC upon cellular stress.
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Mitochondrion membrane;
CC Peripheral membrane protein; Cytoplasmic side. Cytoplasm, cytosol.
CC Microsome. Endoplasmic reticulum. Cytoplasmic vesicle, secretory
CC vesicle, chromaffin granule (By similarity). Note=Isoforms lacking
CC the N-terminal signal sequence have been shown to be cytoplasmic
CC and/or nuclear. Secreted isoforms can retrotranslocate from the
CC secretory compartments to the cytosol upon cellular stress.
CC Detected in perinuclear foci that may be aggresomes containing
CC misfolded, ubiquitinated proteins. Detected at the mitochondrion
CC membrane upon induction of apoptosis.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1; Synonyms=2, CLU35, sCLU;
CC IsoId=P10909-1; Sequence=Displayed;
CC Note=Major isoform;
CC Name=2; Synonyms=1, CLU34;
CC IsoId=P10909-2; Sequence=VSP_037661;
CC Name=3;
CC IsoId=P10909-3; Sequence=VSP_041475;
CC Name=4; Synonyms=nCLU;
CC IsoId=P10909-4; Sequence=VSP_041476;
CC Note=Minor isoform that has been detected in a breast cancer
CC cell line, but not in any other tissues or cell lines;
CC Name=5; Synonyms=CLU36;
CC IsoId=P10909-5; Sequence=VSP_041477;
CC -!- TISSUE SPECIFICITY: Detected in blood plasma, cerebrospinal fluid,
CC milk, seminal plasma and colon mucosa. Detected in the germinal
CC center of colon lymphoid nodules and in colon parasympathetic
CC ganglia of the Auerbach plexus (at protein level). Ubiquitous.
CC Detected in brain, testis, ovary, liver and pancreas, and at lower
CC levels in kidney, heart, spleen and lung.
CC -!- INDUCTION: Up-regulated in response to enterovirus 71 (EV71)
CC infection (at protein level). Up-regulated by agents that induce
CC apoptosis, both at mRNA and protein level. Isoform 1 is up-
CC regulated by androgen. Isoform 2 is down-regulated by androgen.
CC -!- PTM: Isoform 1 is proteolytically cleaved on its way through the
CC secretory system, probably within the Golgi lumen.
CC -!- PTM: Polyubiquitinated, leading to proteasomal degradation.
CC -!- PTM: Heavily N-glycosylated. About 30% of the protein mass is
CC comprised of complex N-linked carbohydrate.
CC -!- SIMILARITY: Belongs to the clusterin family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA35692.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAB06508.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAB06508.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence;
CC Sequence=AAH10514.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAH19588.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAP88927.1; Type=Erroneous gene model prediction;
CC Sequence=AAP88927.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=AAT08041.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=BAG36598.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=CAA32847.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/clu/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/CLUID40107ch8p21.html";
CC -----------------------------------------------------------------------
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DR EMBL; M25915; AAA35692.1; ALT_INIT; mRNA.
DR EMBL; M63379; AAB06507.1; -; Genomic_DNA.
DR EMBL; M63376; AAB06507.1; JOINED; Genomic_DNA.
DR EMBL; M63377; AAB06507.1; JOINED; Genomic_DNA.
DR EMBL; M63378; AAB06507.1; JOINED; Genomic_DNA.
DR EMBL; M64722; AAB06508.1; ALT_SEQ; mRNA.
DR EMBL; AK093399; BAG52708.1; -; mRNA.
DR EMBL; AK313870; BAG36598.1; ALT_INIT; mRNA.
DR EMBL; CR599675; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BX648414; CAI45990.1; -; mRNA.
DR EMBL; AY341244; AAP88927.1; ALT_INIT; Genomic_DNA.
DR EMBL; AF311103; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC010514; AAH10514.1; ALT_INIT; mRNA.
DR EMBL; BC019588; AAH19588.1; ALT_INIT; mRNA.
DR EMBL; BU150467; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; J02908; AAA51765.1; -; mRNA.
DR EMBL; M74816; AAA60321.1; -; mRNA.
DR EMBL; L00974; AAA60567.1; -; Genomic_DNA.
DR EMBL; X14723; CAA32847.1; ALT_INIT; mRNA.
DR EMBL; AY513288; AAT08041.1; ALT_INIT; mRNA.
DR PIR; S43646; A41386.
DR RefSeq; NP_001822.3; NM_001831.3.
DR UniGene; Hs.436657; -.
DR ProteinModelPortal; P10909; -.
DR IntAct; P10909; 28.
DR MINT; MINT-3007494; -.
DR STRING; 9606.ENSP00000315130; -.
DR PhosphoSite; P10909; -.
DR DMDM; 116533; -.
DR DOSAC-COBS-2DPAGE; P10909; -.
DR OGP; P10909; -.
DR REPRODUCTION-2DPAGE; IPI00291262; -.
DR SWISS-2DPAGE; P10909; -.
DR PaxDb; P10909; -.
DR PRIDE; P10909; -.
DR DNASU; 1191; -.
DR Ensembl; ENST00000316403; ENSP00000315130; ENSG00000120885.
DR Ensembl; ENST00000405140; ENSP00000385419; ENSG00000120885.
DR Ensembl; ENST00000523500; ENSP00000429620; ENSG00000120885.
DR Ensembl; ENST00000546343; ENSP00000446413; ENSG00000120885.
DR Ensembl; ENST00000560366; ENSP00000453939; ENSG00000120885.
DR GeneID; 1191; -.
DR KEGG; hsa:1191; -.
DR UCSC; uc003xfw.2; human.
DR CTD; 1191; -.
DR GeneCards; GC08M027454; -.
DR HGNC; HGNC:2095; CLU.
DR HPA; CAB000476; -.
DR HPA; CAB016253; -.
DR HPA; HPA000572; -.
DR MIM; 185430; gene.
DR neXtProt; NX_P10909; -.
DR PharmGKB; PA26620; -.
DR eggNOG; NOG26650; -.
DR HOVERGEN; HBG006908; -.
DR InParanoid; P10909; -.
DR KO; K17252; -.
DR OMA; KFYARVC; -.
DR OrthoDB; EOG7K6PV4; -.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; CLU; human.
DR GeneWiki; Clusterin; -.
DR GenomeRNAi; 1191; -.
DR NextBio; 4922; -.
DR PMAP-CutDB; P10909; -.
DR PRO; PR:P10909; -.
DR ArrayExpress; P10909; -.
DR Bgee; P10909; -.
DR CleanEx; HS_CLU; -.
DR Genevestigator; P10909; -.
DR GO; GO:0042583; C:chromaffin granule; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0031966; C:mitochondrial membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:BHF-UCL.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0034366; C:spherical high-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0051787; F:misfolded protein binding; IDA:UniProtKB.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IDA:UniProtKB.
DR GO; GO:0061077; P:chaperone-mediated protein folding; IDA:UniProtKB.
DR GO; GO:0006956; P:complement activation; TAS:ProtInc.
DR GO; GO:0006958; P:complement activation, classical pathway; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:0006629; P:lipid metabolic process; NAS:ProtInc.
DR GO; GO:1902230; P:negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage; IMP:BHF-UCL.
DR GO; GO:0032463; P:negative regulation of protein homooligomerization; IMP:BHF-UCL.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IMP:UniProtKB.
DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:2000060; P:positive regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; IDA:UniProtKB.
DR GO; GO:0001836; P:release of cytochrome c from mitochondria; IC:BHF-UCL.
DR GO; GO:0051788; P:response to misfolded protein; IDA:BHF-UCL.
DR GO; GO:0009615; P:response to virus; IEP:UniProtKB.
DR GO; GO:0043691; P:reverse cholesterol transport; TAS:BHF-UCL.
DR InterPro; IPR016016; Clusterin.
DR InterPro; IPR000753; Clusterin-like.
DR InterPro; IPR016015; Clusterin_C.
DR InterPro; IPR016014; Clusterin_N.
DR PANTHER; PTHR10970:SF1; PTHR10970:SF1; 1.
DR Pfam; PF01093; Clusterin; 1.
DR PIRSF; PIRSF002368; Clusterin; 1.
DR SMART; SM00035; CLa; 1.
DR SMART; SM00030; CLb; 1.
DR PROSITE; PS00492; CLUSTERIN_1; 1.
DR PROSITE; PS00493; CLUSTERIN_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Apoptosis; Chaperone; Complement pathway;
KW Complete proteome; Cytoplasm; Cytoplasmic vesicle;
KW Direct protein sequencing; Disulfide bond; Endoplasmic reticulum;
KW Glycoprotein; Immunity; Innate immunity; Membrane; Microsome;
KW Mitochondrion; Nucleus; Polymorphism; Reference proteome; Secreted;
KW Signal; Ubl conjugation.
FT SIGNAL 1 22
FT CHAIN 23 449 Clusterin.
FT /FTId=PRO_0000005529.
FT CHAIN 23 227 Clusterin beta chain.
FT /FTId=PRO_0000005530.
FT CHAIN 228 449 Clusterin alpha chain.
FT /FTId=PRO_0000005531.
FT MOTIF 78 81 Nuclear localization signal (By
FT similarity).
FT MOTIF 443 447 Nuclear localization signal (By
FT similarity).
FT CARBOHYD 86 86 N-linked (GlcNAc...) (complex).
FT CARBOHYD 103 103 N-linked (GlcNAc...).
FT CARBOHYD 145 145 N-linked (GlcNAc...).
FT CARBOHYD 291 291 N-linked (GlcNAc...).
FT CARBOHYD 317 317 N-linked (GlcNAc...).
FT CARBOHYD 354 354 N-linked (GlcNAc...).
FT CARBOHYD 374 374 N-linked (GlcNAc...) (complex).
FT DISULFID 102 313 Interchain (between beta and alpha
FT chains).
FT DISULFID 113 305 Interchain (between beta and alpha
FT chains).
FT DISULFID 116 302 Interchain (between beta and alpha
FT chains).
FT DISULFID 121 295 Interchain (between beta and alpha
FT chains).
FT DISULFID 129 285 Interchain (between beta and alpha
FT chains).
FT VAR_SEQ 1 175 Missing (in isoform 3).
FT /FTId=VSP_041475.
FT VAR_SEQ 1 33 Missing (in isoform 4).
FT /FTId=VSP_041476.
FT VAR_SEQ 1 1 M -> MQVCSQPQRGCVREQSAINTAPPSAHNAASPGGARG
FT HRVPLTEACKDSRIGGM (in isoform 2).
FT /FTId=VSP_037661.
FT VAR_SEQ 1 1 M -> MEACKDSRIGGM (in isoform 5).
FT /FTId=VSP_041477.
FT VARIANT 317 317 N -> H (in dbSNP:rs9331936).
FT /FTId=VAR_019366.
FT VARIANT 328 328 D -> N (in dbSNP:rs9331938).
FT /FTId=VAR_019367.
FT VARIANT 396 396 S -> L (in dbSNP:rs13494).
FT /FTId=VAR_019368.
FT CONFLICT 28 28 D -> S (in Ref. 9; AA sequence and 13; AA
FT sequence).
FT CONFLICT 47 47 Q -> H (in Ref. 10; AA sequence).
FT CONFLICT 52 52 G -> Q (in Ref. 10; AA sequence).
FT CONFLICT 172 172 M -> V (in Ref. 5; CAI45990).
FT CONFLICT 224 224 R -> L (in Ref. 3; BAG36598).
FT CONFLICT 305 305 C -> M (in Ref. 9; AA sequence).
FT CONFLICT 388 388 T -> M (in Ref. 5; CAI45990).
FT CONFLICT 411 411 D -> G (in Ref. 3; BAG36598).
SQ SEQUENCE 449 AA; 52495 MW; 9583DE4CCECC169F CRC64;
MMKTLLLFVG LLLTWESGQV LGDQTVSDNE LQEMSNQGSK YVNKEIQNAV NGVKQIKTLI
EKTNEERKTL LSNLEEAKKK KEDALNETRE SETKLKELPG VCNETMMALW EECKPCLKQT
CMKFYARVCR SGSGLVGRQL EEFLNQSSPF YFWMNGDRID SLLENDRQQT HMLDVMQDHF
SRASSIIDEL FQDRFFTREP QDTYHYLPFS LPHRRPHFFF PKSRIVRSLM PFSPYEPLNF
HAMFQPFLEM IHEAQQAMDI HFHSPAFQHP PTEFIREGDD DRTVCREIRH NSTGCLRMKD
QCDKCREILS VDCSTNNPSQ AKLRRELDES LQVAERLTRK YNELLKSYQW KMLNTSSLLE
QLNEQFNWVS RLANLTQGED QYYLRVTTVA SHTSDSDVPS GVTEVVVKLF DSDPITVTVP
VEVSRKNPKF METVAEKALQ EYRKKHREE
//
MIM
185430
*RECORD*
*FIELD* NO
185430
*FIELD* TI
*185430 CLUSTERIN; CLU
;;SULFATED GLYCOPROTEIN 2; SGP2;;
APOLIPOPROTEIN J; APOJ;;
COMPLEMENT-ASSOCIATED PROTEIN SP-40,40;;
read moreCOMPLEMENT LYSIS INHIBITOR; CLI;;
TESTOSTERONE-REPRESSED PROSTATE MESSAGE 2; TRPM2
*FIELD* TX
CLONING
Murphy et al. (1988) described a novel serum protein, SP-40,40, using a
series of monoclonal antibodies directed to the immune
deposit-containing glomerular basement membranes of a patient with
membranous glomerulonephritis. The protein was shown to be a normal
constituent of human blood. It consists of two 40-kD chains, alpha and
beta, covalently joined by disulfide bonds. They established that
SP-40,40 is a member of the human complement system by directly
demonstrating its presence within the S-protein-containing soluble
variant of the C5b-9 complex, SC5b-9. SP-40,40 is also called complement
lysis inhibitor or clusterin. It acts as a control mechanism of the
complement cascade; specifically, it prevents the binding of a C5b-C7
complex to the membrane of the target cell and in this way inhibits
complement-mediated cytolysis.
Kirszbaum et al. (1989) cloned a cDNA for the SP-40,40 protein. They
showed that the 2 chains are coded in a single open reading frame on the
same mRNA molecule, indicating that a precursor protein matures
postsynthetically by the proteolysis of at least 1 peptide bond. They
found that the sequence of the SP-40,40 precursor has 77% identity with
rat sulfated glycoprotein-2 (SGP2), which is the major secreted product
of Sertoli cells. They demonstrated the presence of SP-40,40 within
human seminal plasma at levels comparable to those in serum, indicating
that SP-40,40 and SGP2 are serum and seminal forms of the same protein.
A sequence of 23 amino acids within the beta-chain of SP-40,40 showed
significant homology to corresponding segments in C7, C8, and C9. The
findings of Kirszbaum et al. (1989) document a link between the immune
and reproductive systems.
O'Bryan et al. (1990) reported the purification and characterization of
human seminal clusterin. There is reason to think that
testosterone-repressed prostate message-2 is coded by the same gene
(Purrello et al., 1991). Comparison of the multiple functions suggests
involvement of this protein in the cascade of events leading to
programmed cell death.
Apolipoprotein J is another name for the human analog of the rat protein
SGF2. Its primary structure was deduced by de Silva et al. (1990) using
the combined strategies of protein sequencing and cDNA cloning and
sequencing. It is a 70-kD protein associated with high-density
lipoproteins (HDL) in human plasma. There is a single copy of the APOJ
gene in the human and mouse genomes. The protein is synthesized as a
427-amino acid polypeptide that is posttranslationally cleaved at an
internal bond between arg205 and ser206. Two subunits, designated alpha
(34 to 36 kD), corresponding to residues 1-205, and beta (36 to 39 kD),
corresponding to residues 206-427, are associated through disulfide
bonds. Studies indicated that the alpha and beta subunits are derived
from a common precursor by proteolytic cleavage and that the subunits,
while distinct, have limited regions of homology. De Silva et al. (1990)
found APOJ mRNA (1.9 kb) in all but one tissue examined. Its
concentration was relatively high in brain, ovary, testis, and liver,
lower in heart, spleen, lung, and breast, and absent in T lymphocytes.
Apolipoprotein J is distinct from other known apolipoproteins in
molecular weight, subunit structure, and isoelectric point.
MAPPING
By Southern analysis of somatic cell hybrids, Purrello et al. (1991)
concluded that a single gene is responsible for the multiple functions
of sulfated glycoprotein-2 and that the SGP2 gene is located on human
chromosome 8. Slawin et al. (1990) also mapped SGP2 to chromosome 8 by
Southern analysis of hamster-human hybrid cell lines. Likewise, Tobe et
al. (1991) mapped the CLI gene to human chromosome 8 by spot blot
hybridization of flow-sorted chromosomes using a cDNA probe.
Dietzsch et al. (1992) regionalized the gene to 8p21-p12 by isotopic in
situ hybridization. By fluorescence in situ hybridization, Fink et al.
(1993) showed that CLI is located on 8p21, proximal to the lipoprotein
lipase gene (238600). They cited information suggesting that the CLI
gene may be a candidate gene determining susceptibility to
atherosclerosis.
Using RFLVs (restriction fragment length variations) for interspecies
linkage analysis, Birkenmeier et al. (1993) demonstrated that mouse Cli
gene is located on chromosome 14.
GENE STRUCTURE
By isolating and characterizing 3 partially overlapping cosmid clones,
Fink et al. (1993) established the complete physical map of the
clusterin gene which spans about 20 kb.
Wong et al. (1994) reported that the CLU gene is organized into 9 exons,
ranging in size from 47 bp (exon 1) to 412 bp (exon 5), and spanning a
region of 16,580 bp. Southern analysis and fluorescence in situ
hybridization indicated that the clusterin gene is present in single
copy.
GENE FUNCTION
See review of Jenne and Tschopp (1992). Clusterin mRNA is distributed
heterogeneously in the central nervous system with highest levels in
ependymal cells, as well as in some neurons of the hypothalamus,
brainstem, hebenula, and ventral horn of the spinal cord. It has been
hypothesized to be involved with ongoing synapse turnover (Danik et al.,
1993). Wong et al. (1993) hypothesized that clusterin may be a suicide
gene active in programmed cell death. Dragunow et al. (1995) studied
expression of clusterin immunoreactivity after induction of status
epilepticus. Massive clusterin-like immunoreactivity was observed in CA1
pyramidal cells and dentate hilar neurons, both neuronal populations
destined to die after status epilepticus.
Duguid et al. (1989) found that SGP2 mRNA is synthesized at high levels
in degenerating hippocampus from individuals with Alzheimer disease or
Pick disease. Bertrand et al. (1995) used Western blot analysis to
examine levels of apolipoprotein E and apolipoprotein J (clusterin) in
the brains of Alzheimer disease subjects. The allele dose of
apolipoprotein E4 was correlated with the reduction of apoE levels and
an increase in apolipoprotein J (clusterin) levels, suggesting
compensatory induction of apoJ by those subjects showing low levels of
apoE.
In a series of animal experiments, Navab et al. (1997) demonstrated that
the ratio of APOJ to PON (168820) was increased in fatty
streak-susceptible mice fed an atherogenic diet, in APOE knockout mice
on a chow diet, in LDL receptor knockout mice on a cholesterol-enriched
diet, and in fatty streak-susceptible mice injected with mildly oxidized
LDL fed a chow diet. Human studies showed that the APOJ/PON ratio was
significantly higher than that of controls in 14 normolipemic patients
with coronary artery disease in whom the cholesterol/HDL ratio did not
differ significantly from that of controls.
Ostermeier et al. (2004) showed that human male gametes pass over more
to the oocyte than just the haploid male genome--paternal mRNAs are also
delivered to the egg at fertilization. Ostermeier et al. (2004) used
RT-PCR to identify which transcripts are present in human spermatozoa
but not in unfertilized human oocytes and identified 6 candidates. The
implication is that the spermatozoa deliver these transcripts to the
ooplasm at fertilization. Using the zona-free hamster egg/human sperm
penetration assay to investigate this possibility, Ostermeier et al.
(2004) consistently detected only protamine-2 (182890) and clusterin
transcripts in spermatozoa, zygotes, and in the positive control, and
not in hamster oocytes or in the negative control. These results
demonstrated that spermatozoa deliver RNAs to the oocyte at
fertilization. Ostermeier et al. (2004) suggested that sperm RNAs could
be important in early zygotic and embryonic development and that they
may hold the key to more successful somatic-cell nuclear transfer or to
the identification of male-derived factors that underlie idiopathic
infertility.
CLU is overexpressed in human prostate and breast cancers and in
squamous cell carcinomas, and suppression of CLU renders these cells
sensitive to chemotherapeutic drug-mediated apoptosis. Zhang et al.
(2005) found that intracellular CLU inhibited apoptosis by interfering
with BAX (600040) activation in mitochondria. CLU specifically
interacted with BAX that was conformationally altered by
chemotherapeutic drugs, and the interaction inhibited BAX-mediated
apoptosis. Zhang et al. (2005) concluded that elevated CLU levels in
human cancers may promote oncogenic transformation and tumor progression
by interfering with BAX proapoptotic activities.
Zenkel et al. (2006) provided evidence for a selective downregulation of
expression of clusterin in anterior segment tissues and significantly
reduced aqueous levels of clusterin in eyes of patients with
pseudoexfoliation syndrome (XFS; 177650). The expression of clusterin
was significantly downregulated by TGFB1 (190180) in vitro, providing a
possible explanation for this downregulation. Zenkel et al. (2006)
suggested that the accumulation of the characteristic pathologic matrix
product in XFS eyes may partly arise from stress-induced protein
misfolding and aggregation promoted by a deficiency of clusterin.
MOLECULAR GENETICS
By means of isoelectric focusing and immunoblotting techniques, Kamboh
et al. (1991) demonstrated a common 2-allele polymorphism in populations
with African ancestry. APOJ was found to be monomorphic in US whites,
Amerindians, Eskimos, and New Guineans. In US blacks the frequencies of
the APOJ*1 and APOJ*2 alleles were 0.76 and 0.24, respectively; in
Nigerian blacks, these values were 0.72 and 0.28, respectively. They
found no significant impact of the APOJ polymorphism on total
cholesterol, LDL-cholesterol, HDL-cholesterol, HDL3-cholesterol,
HDL2-cholesterol, VLDL-cholesterol, and triglycerides.
For a discussion of a possible association between variation in the CLU
gene and Alzheimer disease, see 104300.
ANIMAL MODEL
Following neonatal hypoxic-ischemic brain injury in mice (a model of
cerebral palsy), there is evidence of apoptotic changes such as
activation of neuronal caspase-3 (600636), as well as an accumulation of
clusterin in dying neurons. Han et al. (2001) generated mice deficient
in clusterin by targeted disruption. Clusterin -/- mice had 50% less
brain injury following neonatal hypoxia-ischemia. The absence of
clusterin had no effect on caspase-3 activation, and clusterin
accumulation and caspase-3 activation did not colocalize to the same
cells. Studies with cultured cortical neurons demonstrated that
exogenous purified astrocyte-secreted clusterin exacerbated
oxygen/glucose-deprivation-induced necrotic death. Han et al. (2001)
concluded that clusterin may be a therapeutic target to modulate
noncaspase-dependent neuronal death following acute brain injury.
ApoJ is induced in myocarditis and numerous other inflammatory injuries.
To test its ability to modify myosin-induced autoimmune myocarditis,
McLaughlin et al. (2000) generated apoJ-deficient mice. Deficient and
wildtype mice exhibited similar initial onset of myocarditis.
Furthermore, autoantibodies against the primary antigen cardiac myosin
were induced to the same extent. Although the same proportion of
challenged mice exhibited some degree of inflammatory infiltrate,
inflammation was more severe in these mice. Inflammatory lesions were
more diffuse and extensive in deficient mice, particularly in females.
In marked contrast to wildtype mice, the development of a strong
generalized secondary response against cardiac antigens in the deficient
mice was predictive of severe myocarditis. Wildtype mice with a strong
antibody response to secondary antigens appeared to be protected from
severe inflammation. After resolution of inflammation, apoJ-deficient,
but not wildtype, mice exhibited cardiac function impairment and severe
myocardial scarring. These results suggested that apoJ normally limits
progression of autoimmune myocarditis and protects the heart from
postinflammatory tissue destruction.
Chen et al. (2003) sought to discover candidate biomarkers without the
restrictive choice of markers placed on microarrays, and without the
biologic complications of genetic and environmental heterogeneity. They
compared by cDNA subtraction 2 genetically matched sets of mice, 1
developing multiple intestinal neoplasia due to the Min mutation in the
Apc gene and the other the mutation-free parent strain, C57BL/6J. One
prominent candidate biomarker, clusterin, was then subjected to a series
of validation steps. Elevated clusterin expression was characterized
within certain regions of murine and human tumors regardless of tumor
stage, location, or mode of initiation. Cells showing high clusterin
levels generally lacked differentiation markers and adenomatous
polyposis coli antigen. Tumor cells undergoing apoptosis expressed low
levels of clusterin. Its specific expression patterns and correlation
with cellular events during tumorigenesis made it a useful diagnostic
tool in the mouse and a potential contributor to the set of biomarkers
for early detection of human colon cancer.
DeMattos et al. (2004) generated transgenic mice with a mutation in the
amyloid precursor protein (APP) (V717F; 104760.0003) that were also null
for apoE (107741), apoJ, or null for both apo genes. The double apo
knockout mice showed early-onset beta-amyloid deposition beginning at 6
months of age and a marked increase in amyloid deposition compared to
the other mice. The amyloid plaques were compact and diffuse, were
thioflavine S-positive (indicating true fibrillar amyloid), and were
distributed throughout the hippocampus and some parts of the cortex,
contributing to neuritic plaques. The findings suggested that apoE and
apoJ are not required for amyloid fibril formation. The double apo
knockout mice also had increased levels of intracellular soluble
beta-amyloid compared to the other mice. Insoluble beta-42 was similar
to the apoE-null mice, suggesting that ApoE has a selective effect on
beta-42. As APP is produced and secreted by neurons in the CNS and apoE
and clusterin are produced and secreted primarily by astrocytes in the
CNS, the interaction between the apolipoproteins and beta-amyloid occurs
in the interstitial fluid of the brain, an extracellular compartment
that is continuous with the CSF. DeMattos et al. (2004) found that
apoE-null and apoE/apoJ-null mice had increased levels of beta-amyloid
in the CSF and interstitial space, suggesting that apoE, and perhaps
apoJ, play a role in regulating extracellular CNS beta-amyloid clearance
independent of beta-amyloid synthesis. The data suggested that, in the
mouse, apoE and apoJ cooperatively suppress beta-amyloid deposition.
*FIELD* RF
1. Bertrand, P.; Poirier, J.; Oda, T.; Finch, C. E.; Pasinetti, G.
M.: Association of apolipoprotein E genotype with brain levels of
apolipoprotein E and apolipoprotein J (clusterin) in Alzheimer disease. Molec.
Brain Res. 33: 174-178, 1995.
2. Birkenmeier, E. H.; Letts, V. A.; Frankel, W. N.; Magenheimer,
B. S.; Calvet, J. P.: Sulfated glycoprotein-2 (Sgp-2) maps to mouse
chromosome 14. Mammalian Genome 4: 131-132, 1993. Note: Erratum:
Mammalian Genome 4: 238 only, 1993.
3. Chen, X.; Halberg, R. B.; Ehrhardt, W. M.; Torrealba, J.; Dove,
W. F.: Clusterin as a biomarker in murine and human intestinal neoplasia. Proc.
Nat. Acad. Sci. 100: 9530-9535, 2003.
4. Danik, M.; Chabot, J.-G.; Hassan-Gonzalez, D.; Suh, M.; Quirion,
R.: Localization of sulfated glycoprotein-2/clusterin mRNA in the
rat brain by in situ hybridization. J. Comp. Neurol. 334: 209-227,
1993.
5. DeMattos, R. B.; Cirrito, J. R.; Parsadanian, M.; May, P. C.; O'Dell,
M. A.; Taylor, J. W.; Harmony, J. A. K.; Aronow, B. J.; Bales, K.
R.; Paul, S. M.; Holtzman, D. M.: ApoE and clusterin cooperatively
suppress A-beta levels and deposition: evidence that ApoE regulates
extracellular A-beta metabolism in vivo. Neuron 41: 193-202, 2004.
6. de Silva, H. V.; Harmony, J. A. K.; Stuart, W. D.; Gil, C. M.;
Robbins, J.: Apolipoprotein J: structure and tissue distribution. Biochemistry 29:
5380-5389, 1990.
7. de Silva, H. V.; Stuart, W. D.; Park, Y. B.; Mao, S. J. T.; Gil,
C. M.; Wetterau, J. R.; Busch, S. J.; Harmony, J. A. K.: Purification
and characterization of apolipoprotein J. J. Biol. Chem. 265: 14292-14297,
1990.
8. Dietzsch, E.; Murphy, B. F.; Kirszbaum, L.; Walker, I. D.; Garson,
O. M.: Regional localization of the gene for clusterin (SP-40,40;
gene symbol CLI) to human chromosome 8p12-p21. Cytogenet. Cell Genet. 61:
178-179, 1992.
9. Dragunow, M.; Preston, K.; Dodd, J.; Young, D.; Lawlor, P.; Christie,
D.: Clusterin accumulates in dying neurons following status epilepticus. Molec.
Brain Res. 32: 279-290, 1995.
10. Duguid, J. R.; Bohmont, C. W.; Liu, N.; Tourtellotte, W. W.:
Changes in brain gene expression shared by scrapie and Alzheimer disease. Proc.
Nat. Acad. Sci. 86: 7260-7264, 1989.
11. Fink, T. M.; Zimmer, M.; Tschopp, J.; Etienne, J.; Jenne, D. E.;
Lichter, P.: Human clusterin (CLI) maps to 8p21 in proximity to the
lipoprotein lipase (LPL) gene. Genomics 16: 526-528, 1993.
12. Han, B. H.; DeMattos, R. B.; Dugan, L. L.; Kim-Han, J. S.; Brendza,
R. P.; Fryer, J. D.; Kierson, M.; Cirrito, J.; Quick, K.; Harmony,
J. A. K.; Aronow, B. J.; Holtzman, D. M.: Clusterin contributes to
caspase-3-independent brain injury following neonatal hypoxia-ischemia. Nature
Med. 7: 338-343, 2001.
13. Jenne, D. E.; Tschopp, J.: Clusterin: the intriguing guises of
a widely expressed glycoprotein. Trends Biochem. Sci. 17: 154-159,
1992.
14. Kamboh, M. I.; Harmony, J. A. K.; Sepehrnia, B.; Nwankwo, M.;
Ferrell, R. E.: Genetic studies of human apolipoproteins. XX. Genetic
polymorphism of apolipoprotein J and its impact on quantitative lipid
traits in normolipidemic subjects. Am. J. Hum. Genet. 49: 1167-1173,
1991.
15. Kirszbaum, L.; Sharpe, J. A.; Murphy, B.; d'Apice, A. J. F.; Classon,
B.; Hudson, P.; Walker, I. D.: Molecular cloning and characterization
of the novel, human complement-associated protein, SP-40,40: a link
between the complement and reproductive systems. EMBO J. 8: 711-718,
1989.
16. McLaughlin, L.; Zhu, G.; Mistry, M.; Ley-Ebert, C.; Stuart, W.
D.; Florio, C. J.; Groen, P. A.; Witt, S. A.; Kimball, T. R.; Witte,
D. P.; Harmony, J. A. K.; Aronow, B. J.: Apolipoprotein J/clusterin
limits the severity of murine autoimmune myocarditis. J. Clin. Invest. 106:
1105-1113, 2000.
17. Murphy, B. F.; Kirszbaum, L.; Walker, I. D.; d'Apice, A. J. F.
: SP-40,40, a newly identified normal human serum protein found in
the SC5b-9 complex of complement and in the immune deposits in glomerulonephritis. J.
Clin. Invest. 81: 1858-1864, 1988.
18. Navab, M.; Hama-Levy, S.; Van Lenten, B. J.; Fonarow, G. C.; Cardinez,
C. J.; Castellani, L. W.; Brennan, M.-L.; Lusis, A. J.; Fogelman,
A. M.; La Du, B. N.: Mildly oxidized LDL induces an increased apolipoprotein
J/paraoxonase ratio. J. Clin. Invest. 99: 2005-2019, 1997. Note:
Erratum: J. Clin. Invest. 99: 3043 only, 1997.
19. O'Bryan, M. K.; Baker, H. W. G.; Saunders, J. R.; Kirszbaum, L.;
Walker, I. D.; Hudson, P.; Liu, D. Y.; Glew, M. D.; d'Apice, A. J.
F.; Murphy, B. F.: Human seminal clusterin (SP-40,40): isolation
and characterization. J. Clin. Invest. 85: 1477-1486, 1990.
20. Ostermeier, G. C.; Miller, D.; Huntriss, J. D.; Diamond, M. P.;
Krawetz, S. A.: Delivering spermatozoan RNA to the oocyte. Nature 429:
154 only, 2004.
21. Purrello, M.; Bettuzzi, S.; Di Pietro, C.; Mirabile, E.; Di Blasi,
M.; Rimini, R.; Grzeschik, K.-H.; Ingletti, C.; Corti, A.; Sichel,
G.: The gene for SP-40,40, human homolog of rat sulfated glycoprotein
2, rat clusterin, and rat testosterone-repressed prostate message
2, maps to chromosome 8. Genomics 10: 151-156, 1991.
22. Slawin, K.; Sawczuk, I. S.; Olsson, C. A.; Buttyan, R.: Chromosomal
assignment of the human homologue encoding SGP-2. Biochem. Biophys.
Res. Commun. 172: 160-164, 1990.
23. Tobe, T.; Minoshima, S.; Yamase, S.; Choi, N.-H.; Tomita, M.;
Shimizu, N.: Assignment of a human serum glycoprotein SP-40,40 gene
(CLI) to chromosome 8. Cytogenet. Cell Genet. 57: 193-195, 1991.
24. Wong, P.; Pineault, J.; Lakins, J.; Taillefer, D.; Leger, J.;
Wang, C.; Tenniswood, M.: Genomic organization and expression of
the rat TRPM-2 (clusterin) gene, a gene implicated in apoptosis. J.
Biol. Chem. 268: 5021-5031, 1993.
25. Wong, P.; Taillefer, D.; Lakins, J.; Pineault, J.; Chader, G.;
Tenniswood, M.: Molecular characterization of human TRPM-2/clusterin,
a gene associated with sperm maturation, apoptosis and neurodegeneration. Europ.
J. Biochem. 221: 917-925, 1994.
26. Zenkel, M.; Kruse, F. E.; Junemann, A. G.; Naumann, G. O. H.;
Schlotzer-Schrehardt, U.: Clusterin deficiency in eyes with pseudoexfoliation
syndrome may be implicated in the aggregation and deposition of pseudoexfoliative
material. Invest. Ophthal. Vis. Sci. 47: 1982-1990, 2006.
27. Zhang, H.; Kim, J. K.; Edwards, C. A.; Xu, Z.; Taichman, R.; Wang,
C.-Y.: Clusterin inhibits apoptosis by interacting with activated
Bax. Nature Cell Biol. 7: 909-915, 2005.
*FIELD* CN
Jane Kelly - updated: 3/30/2007
Patricia A. Hartz - updated: 12/19/2005
Cassandra L. Kniffin - updated: 3/3/2005
Ada Hamosh - updated: 6/2/2004
Victor A. McKusick - updated: 9/8/2003
Victor A. McKusick - updated: 5/9/2003
Ada Hamosh - updated: 4/4/2001
Michael J. Wright - updated: 9/25/1997
Orest Hurko - updated: 2/5/1996
*FIELD* CD
Victor A. McKusick: 5/13/1989
*FIELD* ED
terry: 03/14/2013
terry: 9/14/2012
alopez: 3/26/2010
carol: 3/30/2007
wwang: 12/19/2005
tkritzer: 3/8/2005
ckniffin: 3/4/2005
ckniffin: 3/3/2005
terry: 2/22/2005
alopez: 6/2/2004
terry: 6/2/2004
cwells: 9/11/2003
terry: 9/8/2003
tkritzer: 5/13/2003
terry: 5/9/2003
alopez: 4/5/2001
terry: 4/4/2001
terry: 8/5/1998
terry: 6/3/1998
alopez: 11/11/1997
terry: 4/15/1996
mark: 2/5/1996
terry: 1/30/1996
carol: 7/20/1994
jason: 7/1/1994
terry: 5/5/1994
carol: 5/26/1993
carol: 2/25/1993
carol: 12/17/1992
*RECORD*
*FIELD* NO
185430
*FIELD* TI
*185430 CLUSTERIN; CLU
;;SULFATED GLYCOPROTEIN 2; SGP2;;
APOLIPOPROTEIN J; APOJ;;
COMPLEMENT-ASSOCIATED PROTEIN SP-40,40;;
read moreCOMPLEMENT LYSIS INHIBITOR; CLI;;
TESTOSTERONE-REPRESSED PROSTATE MESSAGE 2; TRPM2
*FIELD* TX
CLONING
Murphy et al. (1988) described a novel serum protein, SP-40,40, using a
series of monoclonal antibodies directed to the immune
deposit-containing glomerular basement membranes of a patient with
membranous glomerulonephritis. The protein was shown to be a normal
constituent of human blood. It consists of two 40-kD chains, alpha and
beta, covalently joined by disulfide bonds. They established that
SP-40,40 is a member of the human complement system by directly
demonstrating its presence within the S-protein-containing soluble
variant of the C5b-9 complex, SC5b-9. SP-40,40 is also called complement
lysis inhibitor or clusterin. It acts as a control mechanism of the
complement cascade; specifically, it prevents the binding of a C5b-C7
complex to the membrane of the target cell and in this way inhibits
complement-mediated cytolysis.
Kirszbaum et al. (1989) cloned a cDNA for the SP-40,40 protein. They
showed that the 2 chains are coded in a single open reading frame on the
same mRNA molecule, indicating that a precursor protein matures
postsynthetically by the proteolysis of at least 1 peptide bond. They
found that the sequence of the SP-40,40 precursor has 77% identity with
rat sulfated glycoprotein-2 (SGP2), which is the major secreted product
of Sertoli cells. They demonstrated the presence of SP-40,40 within
human seminal plasma at levels comparable to those in serum, indicating
that SP-40,40 and SGP2 are serum and seminal forms of the same protein.
A sequence of 23 amino acids within the beta-chain of SP-40,40 showed
significant homology to corresponding segments in C7, C8, and C9. The
findings of Kirszbaum et al. (1989) document a link between the immune
and reproductive systems.
O'Bryan et al. (1990) reported the purification and characterization of
human seminal clusterin. There is reason to think that
testosterone-repressed prostate message-2 is coded by the same gene
(Purrello et al., 1991). Comparison of the multiple functions suggests
involvement of this protein in the cascade of events leading to
programmed cell death.
Apolipoprotein J is another name for the human analog of the rat protein
SGF2. Its primary structure was deduced by de Silva et al. (1990) using
the combined strategies of protein sequencing and cDNA cloning and
sequencing. It is a 70-kD protein associated with high-density
lipoproteins (HDL) in human plasma. There is a single copy of the APOJ
gene in the human and mouse genomes. The protein is synthesized as a
427-amino acid polypeptide that is posttranslationally cleaved at an
internal bond between arg205 and ser206. Two subunits, designated alpha
(34 to 36 kD), corresponding to residues 1-205, and beta (36 to 39 kD),
corresponding to residues 206-427, are associated through disulfide
bonds. Studies indicated that the alpha and beta subunits are derived
from a common precursor by proteolytic cleavage and that the subunits,
while distinct, have limited regions of homology. De Silva et al. (1990)
found APOJ mRNA (1.9 kb) in all but one tissue examined. Its
concentration was relatively high in brain, ovary, testis, and liver,
lower in heart, spleen, lung, and breast, and absent in T lymphocytes.
Apolipoprotein J is distinct from other known apolipoproteins in
molecular weight, subunit structure, and isoelectric point.
MAPPING
By Southern analysis of somatic cell hybrids, Purrello et al. (1991)
concluded that a single gene is responsible for the multiple functions
of sulfated glycoprotein-2 and that the SGP2 gene is located on human
chromosome 8. Slawin et al. (1990) also mapped SGP2 to chromosome 8 by
Southern analysis of hamster-human hybrid cell lines. Likewise, Tobe et
al. (1991) mapped the CLI gene to human chromosome 8 by spot blot
hybridization of flow-sorted chromosomes using a cDNA probe.
Dietzsch et al. (1992) regionalized the gene to 8p21-p12 by isotopic in
situ hybridization. By fluorescence in situ hybridization, Fink et al.
(1993) showed that CLI is located on 8p21, proximal to the lipoprotein
lipase gene (238600). They cited information suggesting that the CLI
gene may be a candidate gene determining susceptibility to
atherosclerosis.
Using RFLVs (restriction fragment length variations) for interspecies
linkage analysis, Birkenmeier et al. (1993) demonstrated that mouse Cli
gene is located on chromosome 14.
GENE STRUCTURE
By isolating and characterizing 3 partially overlapping cosmid clones,
Fink et al. (1993) established the complete physical map of the
clusterin gene which spans about 20 kb.
Wong et al. (1994) reported that the CLU gene is organized into 9 exons,
ranging in size from 47 bp (exon 1) to 412 bp (exon 5), and spanning a
region of 16,580 bp. Southern analysis and fluorescence in situ
hybridization indicated that the clusterin gene is present in single
copy.
GENE FUNCTION
See review of Jenne and Tschopp (1992). Clusterin mRNA is distributed
heterogeneously in the central nervous system with highest levels in
ependymal cells, as well as in some neurons of the hypothalamus,
brainstem, hebenula, and ventral horn of the spinal cord. It has been
hypothesized to be involved with ongoing synapse turnover (Danik et al.,
1993). Wong et al. (1993) hypothesized that clusterin may be a suicide
gene active in programmed cell death. Dragunow et al. (1995) studied
expression of clusterin immunoreactivity after induction of status
epilepticus. Massive clusterin-like immunoreactivity was observed in CA1
pyramidal cells and dentate hilar neurons, both neuronal populations
destined to die after status epilepticus.
Duguid et al. (1989) found that SGP2 mRNA is synthesized at high levels
in degenerating hippocampus from individuals with Alzheimer disease or
Pick disease. Bertrand et al. (1995) used Western blot analysis to
examine levels of apolipoprotein E and apolipoprotein J (clusterin) in
the brains of Alzheimer disease subjects. The allele dose of
apolipoprotein E4 was correlated with the reduction of apoE levels and
an increase in apolipoprotein J (clusterin) levels, suggesting
compensatory induction of apoJ by those subjects showing low levels of
apoE.
In a series of animal experiments, Navab et al. (1997) demonstrated that
the ratio of APOJ to PON (168820) was increased in fatty
streak-susceptible mice fed an atherogenic diet, in APOE knockout mice
on a chow diet, in LDL receptor knockout mice on a cholesterol-enriched
diet, and in fatty streak-susceptible mice injected with mildly oxidized
LDL fed a chow diet. Human studies showed that the APOJ/PON ratio was
significantly higher than that of controls in 14 normolipemic patients
with coronary artery disease in whom the cholesterol/HDL ratio did not
differ significantly from that of controls.
Ostermeier et al. (2004) showed that human male gametes pass over more
to the oocyte than just the haploid male genome--paternal mRNAs are also
delivered to the egg at fertilization. Ostermeier et al. (2004) used
RT-PCR to identify which transcripts are present in human spermatozoa
but not in unfertilized human oocytes and identified 6 candidates. The
implication is that the spermatozoa deliver these transcripts to the
ooplasm at fertilization. Using the zona-free hamster egg/human sperm
penetration assay to investigate this possibility, Ostermeier et al.
(2004) consistently detected only protamine-2 (182890) and clusterin
transcripts in spermatozoa, zygotes, and in the positive control, and
not in hamster oocytes or in the negative control. These results
demonstrated that spermatozoa deliver RNAs to the oocyte at
fertilization. Ostermeier et al. (2004) suggested that sperm RNAs could
be important in early zygotic and embryonic development and that they
may hold the key to more successful somatic-cell nuclear transfer or to
the identification of male-derived factors that underlie idiopathic
infertility.
CLU is overexpressed in human prostate and breast cancers and in
squamous cell carcinomas, and suppression of CLU renders these cells
sensitive to chemotherapeutic drug-mediated apoptosis. Zhang et al.
(2005) found that intracellular CLU inhibited apoptosis by interfering
with BAX (600040) activation in mitochondria. CLU specifically
interacted with BAX that was conformationally altered by
chemotherapeutic drugs, and the interaction inhibited BAX-mediated
apoptosis. Zhang et al. (2005) concluded that elevated CLU levels in
human cancers may promote oncogenic transformation and tumor progression
by interfering with BAX proapoptotic activities.
Zenkel et al. (2006) provided evidence for a selective downregulation of
expression of clusterin in anterior segment tissues and significantly
reduced aqueous levels of clusterin in eyes of patients with
pseudoexfoliation syndrome (XFS; 177650). The expression of clusterin
was significantly downregulated by TGFB1 (190180) in vitro, providing a
possible explanation for this downregulation. Zenkel et al. (2006)
suggested that the accumulation of the characteristic pathologic matrix
product in XFS eyes may partly arise from stress-induced protein
misfolding and aggregation promoted by a deficiency of clusterin.
MOLECULAR GENETICS
By means of isoelectric focusing and immunoblotting techniques, Kamboh
et al. (1991) demonstrated a common 2-allele polymorphism in populations
with African ancestry. APOJ was found to be monomorphic in US whites,
Amerindians, Eskimos, and New Guineans. In US blacks the frequencies of
the APOJ*1 and APOJ*2 alleles were 0.76 and 0.24, respectively; in
Nigerian blacks, these values were 0.72 and 0.28, respectively. They
found no significant impact of the APOJ polymorphism on total
cholesterol, LDL-cholesterol, HDL-cholesterol, HDL3-cholesterol,
HDL2-cholesterol, VLDL-cholesterol, and triglycerides.
For a discussion of a possible association between variation in the CLU
gene and Alzheimer disease, see 104300.
ANIMAL MODEL
Following neonatal hypoxic-ischemic brain injury in mice (a model of
cerebral palsy), there is evidence of apoptotic changes such as
activation of neuronal caspase-3 (600636), as well as an accumulation of
clusterin in dying neurons. Han et al. (2001) generated mice deficient
in clusterin by targeted disruption. Clusterin -/- mice had 50% less
brain injury following neonatal hypoxia-ischemia. The absence of
clusterin had no effect on caspase-3 activation, and clusterin
accumulation and caspase-3 activation did not colocalize to the same
cells. Studies with cultured cortical neurons demonstrated that
exogenous purified astrocyte-secreted clusterin exacerbated
oxygen/glucose-deprivation-induced necrotic death. Han et al. (2001)
concluded that clusterin may be a therapeutic target to modulate
noncaspase-dependent neuronal death following acute brain injury.
ApoJ is induced in myocarditis and numerous other inflammatory injuries.
To test its ability to modify myosin-induced autoimmune myocarditis,
McLaughlin et al. (2000) generated apoJ-deficient mice. Deficient and
wildtype mice exhibited similar initial onset of myocarditis.
Furthermore, autoantibodies against the primary antigen cardiac myosin
were induced to the same extent. Although the same proportion of
challenged mice exhibited some degree of inflammatory infiltrate,
inflammation was more severe in these mice. Inflammatory lesions were
more diffuse and extensive in deficient mice, particularly in females.
In marked contrast to wildtype mice, the development of a strong
generalized secondary response against cardiac antigens in the deficient
mice was predictive of severe myocarditis. Wildtype mice with a strong
antibody response to secondary antigens appeared to be protected from
severe inflammation. After resolution of inflammation, apoJ-deficient,
but not wildtype, mice exhibited cardiac function impairment and severe
myocardial scarring. These results suggested that apoJ normally limits
progression of autoimmune myocarditis and protects the heart from
postinflammatory tissue destruction.
Chen et al. (2003) sought to discover candidate biomarkers without the
restrictive choice of markers placed on microarrays, and without the
biologic complications of genetic and environmental heterogeneity. They
compared by cDNA subtraction 2 genetically matched sets of mice, 1
developing multiple intestinal neoplasia due to the Min mutation in the
Apc gene and the other the mutation-free parent strain, C57BL/6J. One
prominent candidate biomarker, clusterin, was then subjected to a series
of validation steps. Elevated clusterin expression was characterized
within certain regions of murine and human tumors regardless of tumor
stage, location, or mode of initiation. Cells showing high clusterin
levels generally lacked differentiation markers and adenomatous
polyposis coli antigen. Tumor cells undergoing apoptosis expressed low
levels of clusterin. Its specific expression patterns and correlation
with cellular events during tumorigenesis made it a useful diagnostic
tool in the mouse and a potential contributor to the set of biomarkers
for early detection of human colon cancer.
DeMattos et al. (2004) generated transgenic mice with a mutation in the
amyloid precursor protein (APP) (V717F; 104760.0003) that were also null
for apoE (107741), apoJ, or null for both apo genes. The double apo
knockout mice showed early-onset beta-amyloid deposition beginning at 6
months of age and a marked increase in amyloid deposition compared to
the other mice. The amyloid plaques were compact and diffuse, were
thioflavine S-positive (indicating true fibrillar amyloid), and were
distributed throughout the hippocampus and some parts of the cortex,
contributing to neuritic plaques. The findings suggested that apoE and
apoJ are not required for amyloid fibril formation. The double apo
knockout mice also had increased levels of intracellular soluble
beta-amyloid compared to the other mice. Insoluble beta-42 was similar
to the apoE-null mice, suggesting that ApoE has a selective effect on
beta-42. As APP is produced and secreted by neurons in the CNS and apoE
and clusterin are produced and secreted primarily by astrocytes in the
CNS, the interaction between the apolipoproteins and beta-amyloid occurs
in the interstitial fluid of the brain, an extracellular compartment
that is continuous with the CSF. DeMattos et al. (2004) found that
apoE-null and apoE/apoJ-null mice had increased levels of beta-amyloid
in the CSF and interstitial space, suggesting that apoE, and perhaps
apoJ, play a role in regulating extracellular CNS beta-amyloid clearance
independent of beta-amyloid synthesis. The data suggested that, in the
mouse, apoE and apoJ cooperatively suppress beta-amyloid deposition.
*FIELD* RF
1. Bertrand, P.; Poirier, J.; Oda, T.; Finch, C. E.; Pasinetti, G.
M.: Association of apolipoprotein E genotype with brain levels of
apolipoprotein E and apolipoprotein J (clusterin) in Alzheimer disease. Molec.
Brain Res. 33: 174-178, 1995.
2. Birkenmeier, E. H.; Letts, V. A.; Frankel, W. N.; Magenheimer,
B. S.; Calvet, J. P.: Sulfated glycoprotein-2 (Sgp-2) maps to mouse
chromosome 14. Mammalian Genome 4: 131-132, 1993. Note: Erratum:
Mammalian Genome 4: 238 only, 1993.
3. Chen, X.; Halberg, R. B.; Ehrhardt, W. M.; Torrealba, J.; Dove,
W. F.: Clusterin as a biomarker in murine and human intestinal neoplasia. Proc.
Nat. Acad. Sci. 100: 9530-9535, 2003.
4. Danik, M.; Chabot, J.-G.; Hassan-Gonzalez, D.; Suh, M.; Quirion,
R.: Localization of sulfated glycoprotein-2/clusterin mRNA in the
rat brain by in situ hybridization. J. Comp. Neurol. 334: 209-227,
1993.
5. DeMattos, R. B.; Cirrito, J. R.; Parsadanian, M.; May, P. C.; O'Dell,
M. A.; Taylor, J. W.; Harmony, J. A. K.; Aronow, B. J.; Bales, K.
R.; Paul, S. M.; Holtzman, D. M.: ApoE and clusterin cooperatively
suppress A-beta levels and deposition: evidence that ApoE regulates
extracellular A-beta metabolism in vivo. Neuron 41: 193-202, 2004.
6. de Silva, H. V.; Harmony, J. A. K.; Stuart, W. D.; Gil, C. M.;
Robbins, J.: Apolipoprotein J: structure and tissue distribution. Biochemistry 29:
5380-5389, 1990.
7. de Silva, H. V.; Stuart, W. D.; Park, Y. B.; Mao, S. J. T.; Gil,
C. M.; Wetterau, J. R.; Busch, S. J.; Harmony, J. A. K.: Purification
and characterization of apolipoprotein J. J. Biol. Chem. 265: 14292-14297,
1990.
8. Dietzsch, E.; Murphy, B. F.; Kirszbaum, L.; Walker, I. D.; Garson,
O. M.: Regional localization of the gene for clusterin (SP-40,40;
gene symbol CLI) to human chromosome 8p12-p21. Cytogenet. Cell Genet. 61:
178-179, 1992.
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*FIELD* CN
Jane Kelly - updated: 3/30/2007
Patricia A. Hartz - updated: 12/19/2005
Cassandra L. Kniffin - updated: 3/3/2005
Ada Hamosh - updated: 6/2/2004
Victor A. McKusick - updated: 9/8/2003
Victor A. McKusick - updated: 5/9/2003
Ada Hamosh - updated: 4/4/2001
Michael J. Wright - updated: 9/25/1997
Orest Hurko - updated: 2/5/1996
*FIELD* CD
Victor A. McKusick: 5/13/1989
*FIELD* ED
terry: 03/14/2013
terry: 9/14/2012
alopez: 3/26/2010
carol: 3/30/2007
wwang: 12/19/2005
tkritzer: 3/8/2005
ckniffin: 3/4/2005
ckniffin: 3/3/2005
terry: 2/22/2005
alopez: 6/2/2004
terry: 6/2/2004
cwells: 9/11/2003
terry: 9/8/2003
tkritzer: 5/13/2003
terry: 5/9/2003
alopez: 4/5/2001
terry: 4/4/2001
terry: 8/5/1998
terry: 6/3/1998
alopez: 11/11/1997
terry: 4/15/1996
mark: 2/5/1996
terry: 1/30/1996
carol: 7/20/1994
jason: 7/1/1994
terry: 5/5/1994
carol: 5/26/1993
carol: 2/25/1993
carol: 12/17/1992