Full text data of PDCD6
PDCD6
(ALG2)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Programmed cell death protein 6 (Apoptosis-linked gene 2 protein; Probable calcium-binding protein ALG-2)
Programmed cell death protein 6 (Apoptosis-linked gene 2 protein; Probable calcium-binding protein ALG-2)
hRBCD
IPI00025277
IPI00025277 Programmed cell death protein 6 Programmed cell death protein 6 membrane n/a 1 n/a n/a n/a n/a n/a n/a 5 n/a n/a n/a n/a n/a n/a n/a n/a 2 2 2 not mentioned n/a found at its expected molecular weight found at molecular weight
IPI00025277 Programmed cell death protein 6 Programmed cell death protein 6 membrane n/a 1 n/a n/a n/a n/a n/a n/a 5 n/a n/a n/a n/a n/a n/a n/a n/a 2 2 2 not mentioned n/a found at its expected molecular weight found at molecular weight
UniProt
O75340
ID PDCD6_HUMAN Reviewed; 191 AA.
AC O75340; B2RD16; E7ESR3; Q2YDC2; Q5TZS0;
DT 11-JAN-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1998, sequence version 1.
DT 22-JAN-2014, entry version 130.
DE RecName: Full=Programmed cell death protein 6;
DE AltName: Full=Apoptosis-linked gene 2 protein;
DE AltName: Full=Probable calcium-binding protein ALG-2;
GN Name=PDCD6; Synonyms=ALG2;
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).
RA Ganjei J.K., D'Adamio L.;
RL Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RA Urcelay E., Ibarreta D., Parrilla R., Ayuso M.S.;
RL Submitted (MAY-1996) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Cerebellum;
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 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3).
RC TISSUE=Colon, Ovary, and Placenta;
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 [8]
RP INTERACTION WITH PEF1.
RX PubMed=11278427; DOI=10.1074/jbc.M008649200;
RA Kitaura Y., Matsumoto S., Satoh H., Hitomi K., Maki M.;
RT "Peflin and ALG-2, members of the penta-EF-hand protein family, form a
RT heterodimer that dissociates in a Ca2+-dependent manner.";
RL J. Biol. Chem. 276:14053-14058(2001).
RN [9]
RP INTERACTION WITH PEF1.
RX PubMed=11883899; DOI=10.1006/abbi.2001.2736;
RA Kitaura Y., Satoh H., Takahashi H., Shibata H., Maki M.;
RT "Both ALG-2 and peflin, penta-EF-hand (PEF) proteins, are stabilized
RT by dimerization through their fifth EF-hand regions.";
RL Arch. Biochem. Biophys. 399:12-18(2002).
RN [10]
RP INTERACTION WITH ANXA11.
RX PubMed=11883939; DOI=10.1006/bbrc.2002.6600;
RA Satoh H., Shibata H., Nakano Y., Kitaura Y., Maki M.;
RT "ALG-2 interacts with the amino-terminal domain of annexin XI in a
RT Ca(2+)-dependent manner.";
RL Biochem. Biophys. Res. Commun. 291:1166-1172(2002).
RN [11]
RP FUNCTION, AND INTERACTION WITH DAPK1.
RX PubMed=16132846; DOI=10.1007/s10529-005-7869-x;
RA Lee J.H., Rho S.B., Chun T.;
RT "Programmed cell death 6 (PDCD6) protein interacts with death-
RT associated protein kinase 1 (DAPk1): additive effect on apoptosis via
RT caspase-3 dependent pathway.";
RL Biotechnol. Lett. 27:1011-1015(2005).
RN [12]
RP INTERACTION WITH RBM22.
RX PubMed=17045351; DOI=10.1016/j.bbamcr.2006.09.003;
RA Montaville P., Dai Y., Cheung C.Y., Giller K., Becker S., Michalak M.,
RA Webb S.E., Miller A.L., Krebs J.;
RT "Nuclear translocation of the calcium-binding protein ALG-2 induced by
RT the RNA-binding protein RBM22.";
RL Biochim. Biophys. Acta 1763:1335-1343(2006).
RN [13]
RP INTERACTION WITH SEC31A AND PDCD6IP, MUTAGENESIS OF GLU-47 AND
RP GLU-114, AND SUBCELLULAR LOCATION.
RX PubMed=16957052; DOI=10.1091/mbc.E06-05-0444;
RA Yamasaki A., Tani K., Yamamoto A., Kitamura N., Komada M.;
RT "The Ca2+-binding protein ALG-2 is recruited to endoplasmic reticulum
RT exit sites by Sec31A and stabilizes the localization of Sec31A.";
RL Mol. Biol. Cell 17:4876-4887(2006).
RN [14]
RP FUNCTION, AND INTERACTION WITH WITH SHISA5.
RX PubMed=17889823; DOI=10.1016/j.abb.2007.07.028;
RA Draeby I., Woods Y.L., la Cour J.M., Mollerup J., Bourdon J.C.,
RA Berchtold M.W.;
RT "The calcium binding protein ALG-2 binds and stabilizes Scotin, a p53-
RT inducible gene product localized at the endoplasmic reticulum
RT membrane.";
RL Arch. Biochem. Biophys. 467:87-94(2007).
RN [15]
RP INTERACTION WITH PLSCR3; PLSCR4; PDCD6IP; ANXA7; ANXA11; SEC31A AND
RP TSG101, AND MUTAGENESIS OF GLU-47; TRP-57; PHE-60; TYR-91; TRP-95;
RP GLU-114 AND TYR-180.
RX PubMed=18256029; DOI=10.1074/jbc.M800717200;
RA Shibata H., Suzuki H., Kakiuchi T., Inuzuka T., Yoshida H., Mizuno T.,
RA Maki M.;
RT "Identification of Alix-type and non-Alix-type ALG-2-binding sites in
RT human phospholipid scramblase 3: differential binding to an
RT alternatively spliced isoform and amino acid-substituted mutants.";
RL J. Biol. Chem. 283:9623-9632(2008).
RN [16]
RP FUNCTION.
RX PubMed=19520058; DOI=10.1016/j.bbrc.2009.06.015;
RA Okumura M., Ichioka F., Kobayashi R., Suzuki H., Yoshida H.,
RA Shibata H., Maki M.;
RT "Penta-EF-hand protein ALG-2 functions as a Ca2+-dependent adaptor
RT that bridges Alix and TSG101.";
RL Biochem. Biophys. Res. Commun. 386:237-241(2009).
RN [17]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH MCOLN1.
RX PubMed=19864416; DOI=10.1074/jbc.M109.047241;
RA Vergarajauregui S., Martina J.A., Puertollano R.;
RT "Identification of the penta-EF-hand protein ALG-2 as a Ca2+-dependent
RT interactor of mucolipin-1.";
RL J. Biol. Chem. 284:36357-36366(2009).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [19]
RP SUBCELLULAR LOCATION.
RX PubMed=21122810; DOI=10.1016/j.bbamcr.2010.11.010;
RA Janowicz A., Michalak M., Krebs J.;
RT "Stress induced subcellular distribution of ALG-2, RBM22 and hSlu7.";
RL Biochim. Biophys. Acta 1813:1045-1049(2011).
RN [20]
RP FUNCTION, AND INTERACTION WITH KDR.
RX PubMed=21893193; DOI=10.1016/j.cellsig.2011.08.013;
RA Rho S.B., Song Y.J., Lim M.C., Lee S.H., Kim B.R., Park S.Y.;
RT "Programmed cell death 6 (PDCD6) inhibits angiogenesis through
RT PI3K/mTOR/p70S6K pathway by interacting of VEGFR-2.";
RL Cell. Signal. 24:131-139(2012).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 24-191 IN COMPLEXES WITH
RP CALCIUM; ZINC AND PDCD6IP, SUBUNIT, AND INTERACTION WITH PDCD6IP.
RX PubMed=18940611; DOI=10.1016/j.str.2008.07.012;
RA Suzuki H., Kawasaki M., Inuzuka T., Okumura M., Kakiuchi T.,
RA Shibata H., Wakatsuki S., Maki M.;
RT "Structural basis for Ca2+ -dependent formation of ALG-2/Alix peptide
RT complex: Ca2+/EF3-driven arginine switch mechanism.";
RL Structure 16:1562-1573(2008).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 24-191, INTERACTION WITH
RP PDCD6IP; TSG101; ANXA7 AND ANXA11, AND MUTAGENESIS OF PHE-122.
RX PubMed=20691033; DOI=10.1186/1472-6807-10-25;
RA Inuzuka T., Suzuki H., Kawasaki M., Shibata H., Wakatsuki S., Maki M.;
RT "Molecular basis for defect in Alix-binding by alternatively spliced
RT isoform of ALG-2 (ALG-2DeltaGF122) and structural roles of F122 in
RT target recognition.";
RL BMC Struct. Biol. 10:25-25(2010).
RN [23]
RP VARIANT [LARGE SCALE ANALYSIS] CYS-123.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Calcium-binding protein required for T-cell receptor-,
CC Fas-, and glucocorticoid-induced cell death. May mediate Ca(2+)-
CC regulated signals along the death pathway (By similarity).
CC Calcium-dependent adapter necessary for the association between
CC PDCD6IP and TSG101. Interaction with DAPK1 can accelerate
CC apoptotic cell death by increasing caspase-3 activity. May inhibit
CC KDR/VEGFR2-dependent angiogenesis; the function involves
CC inhibition of VEGF-induced phosphoprylation of the Akt signaling
CC pathway. Seems to play a role in the regulation of the
CC distribution and function of MCOLN1 in the endosomal pathway.
CC Isoform 2 has a lower Ca(2+) affinity than isoform 1. Isoform 1
CC and, to a lesser extend, isoform 2, can stabilize SHISA5.
CC -!- SUBUNIT: Isoform 1 and isoform 2 self-associate; probably forming
CC homodimers. Interacts with SHISA5, PEF1, RBM22, PLSCR4, ANXA7,
CC TSG101 and DAPK1. Interacts with PDCD6IP, SEC31A, ANXA11 (via N-
CC terminus), PLSCR3 (via N-terminus) and MCOLN1; the interactions
CC are calcium-dependent. Isoform 2 does not interact with SHISA5,
CC PDCD6IP, TSG101, ANXA7 and ANXA11.
CC -!- INTERACTION:
CC P53355:DAPK1; NbExp=3; IntAct=EBI-352915, EBI-358616;
CC P35968:KDR; NbExp=4; IntAct=EBI-352915, EBI-1005487;
CC Q8WUM4:PDCD6IP; NbExp=5; IntAct=EBI-352915, EBI-310624;
CC Q9NRY6:PLSCR3; NbExp=9; IntAct=EBI-352915, EBI-750734;
CC Q9H3S7:PTPN23; NbExp=3; IntAct=EBI-352915, EBI-724478;
CC O94979:SEC31A; NbExp=6; IntAct=EBI-352915, EBI-1767898;
CC -!- SUBCELLULAR LOCATION: Nucleus membrane; Peripheral membrane
CC protein. Endoplasmic reticulum membrane; Peripheral membrane
CC protein. Nucleus. Endosome. Note=Interaction with RBM22 induces
CC relocalization from the cytoplasm to the nucleus. Translocated
CC from the cytoplasm to the nucleus after heat shock cell treatment.
CC Accumulates in cytoplasmic vesicle-like organelles after heat
CC shock treatment, which may represent stress granules.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=O75340-1; Sequence=Displayed;
CC Name=2; Synonyms=ALG-2(delta)GF122;
CC IsoId=O75340-2; Sequence=VSP_045113;
CC Name=3;
CC IsoId=O75340-3; Sequence=VSP_045542;
CC Note=No experimental confirmation available;
CC -!- SIMILARITY: Contains 5 EF-hand domains.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/PDCD6ID43402ch5p15.html";
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DR EMBL; AF035606; AAC27697.1; -; mRNA.
DR EMBL; U58773; AAF14336.1; -; mRNA.
DR EMBL; AK315370; BAG37763.1; -; mRNA.
DR EMBL; BT020072; AAV38875.1; -; mRNA.
DR EMBL; AC010442; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC021087; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC118458; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471235; EAW50991.1; -; Genomic_DNA.
DR EMBL; BC012384; AAH12384.1; -; mRNA.
DR EMBL; BC106706; AAI06707.1; -; mRNA.
DR EMBL; BC110291; AAI10292.1; -; mRNA.
DR EMBL; CB991882; -; NOT_ANNOTATED_CDS; mRNA.
DR RefSeq; NP_001254485.1; NM_001267556.1.
DR RefSeq; NP_001254486.1; NM_001267557.1.
DR RefSeq; NP_001254487.1; NM_001267558.1.
DR RefSeq; NP_001254488.1; NM_001267559.1.
DR RefSeq; NP_037364.1; NM_013232.3.
DR UniGene; Hs.50823; -.
DR PDB; 2ZN8; X-ray; 2.70 A; A=2-191.
DR PDB; 2ZN9; X-ray; 2.40 A; A/B=20-191.
DR PDB; 2ZND; X-ray; 1.70 A; A=20-191.
DR PDB; 2ZNE; X-ray; 2.20 A; A/B=24-191.
DR PDB; 2ZRS; X-ray; 3.10 A; A/B/C/D/E/F/G/H=24-191.
DR PDB; 2ZRT; X-ray; 3.30 A; A/B/C/D/E/F/G/H=24-191.
DR PDB; 3AAJ; X-ray; 2.40 A; A/B=24-191.
DR PDB; 3AAK; X-ray; 2.70 A; A=20-191.
DR PDBsum; 2ZN8; -.
DR PDBsum; 2ZN9; -.
DR PDBsum; 2ZND; -.
DR PDBsum; 2ZNE; -.
DR PDBsum; 2ZRS; -.
DR PDBsum; 2ZRT; -.
DR PDBsum; 3AAJ; -.
DR PDBsum; 3AAK; -.
DR ProteinModelPortal; O75340; -.
DR SMR; O75340; 24-191.
DR DIP; DIP-33217N; -.
DR IntAct; O75340; 30.
DR MINT; MINT-5000341; -.
DR STRING; 9606.ENSP00000323816; -.
DR PhosphoSite; O75340; -.
DR PRIDE; O75340; -.
DR DNASU; 10016; -.
DR Ensembl; ENST00000264933; ENSP00000264933; ENSG00000249915.
DR Ensembl; ENST00000505221; ENSP00000422085; ENSG00000249915.
DR Ensembl; ENST00000507528; ENSP00000423815; ENSG00000249915.
DR GeneID; 10016; -.
DR KEGG; hsa:10016; -.
DR UCSC; uc031sik.1; human.
DR CTD; 10016; -.
DR GeneCards; GC05P000258; -.
DR HGNC; HGNC:8765; PDCD6.
DR MIM; 601057; gene.
DR neXtProt; NX_O75340; -.
DR PharmGKB; PA33115; -.
DR HOGENOM; HOG000231984; -.
DR HOVERGEN; HBG004492; -.
DR OMA; FLWNIFQ; -.
DR OrthoDB; EOG7RV9FM; -.
DR ChiTaRS; PDCD6; human.
DR EvolutionaryTrace; O75340; -.
DR GeneWiki; PDCD6; -.
DR GenomeRNAi; 10016; -.
DR NextBio; 37841; -.
DR PRO; PR:O75340; -.
DR ArrayExpress; O75340; -.
DR Bgee; O75340; -.
DR CleanEx; HS_ALG2; -.
DR CleanEx; HS_PDCD6; -.
DR Genevestigator; O75340; -.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005768; C:endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0031965; C:nuclear membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0060090; F:binding, bridging; IMP:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IEA:Ensembl.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0097190; P:apoptotic signaling pathway; TAS:ProtInc.
DR GO; GO:0033554; P:cellular response to stress; IDA:UniProtKB.
DR GO; GO:0006886; P:intracellular protein transport; IDA:UniProtKB.
DR GO; GO:0051898; P:negative regulation of protein kinase B signaling cascade; IDA:UniProtKB.
DR GO; GO:0032007; P:negative regulation of TOR signaling cascade; IDA:UniProtKB.
DR GO; GO:0030948; P:negative regulation of vascular endothelial growth factor receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IDA:UniProtKB.
DR GO; GO:0010595; P:positive regulation of endothelial cell migration; IDA:UniProtKB.
DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IDA:UniProtKB.
DR GO; GO:0051592; P:response to calcium ion; ISS:UniProtKB.
DR GO; GO:0036324; P:vascular endothelial growth factor receptor-2 signaling pathway; IDA:UniProtKB.
DR Gene3D; 1.10.238.10; -; 1.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR Pfam; PF13499; EF-hand_7; 1.
DR SMART; SM00054; EFh; 5.
DR PROSITE; PS00018; EF_HAND_1; 2.
DR PROSITE; PS50222; EF_HAND_2; 3.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Angiogenesis; Apoptosis; Calcium;
KW Complete proteome; Endoplasmic reticulum; Endosome; Membrane;
KW Metal-binding; Nucleus; Polymorphism; Reference proteome; Repeat.
FT CHAIN 1 191 Programmed cell death protein 6.
FT /FTId=PRO_0000073729.
FT DOMAIN 23 58 EF-hand 1.
FT DOMAIN 59 89 EF-hand 2.
FT DOMAIN 90 125 EF-hand 3.
FT DOMAIN 126 161 EF-hand 4.
FT DOMAIN 162 191 EF-hand 5.
FT CA_BIND 36 47 1.
FT CA_BIND 73 84 2 (Potential).
FT CA_BIND 103 114 3.
FT CA_BIND 169 181 4.
FT VAR_SEQ 70 191 Missing (in isoform 3).
FT /FTId=VSP_045542.
FT VAR_SEQ 121 122 Missing (in isoform 2).
FT /FTId=VSP_045113.
FT VARIANT 123 123 G -> C (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035459.
FT MUTAGEN 47 47 E->A: Loss of interaction with SEC31A and
FT PLSCR3, and loss of localization to the
FT endoplasmic reticulum; when associated
FT with A-114.
FT MUTAGEN 57 57 W->A: Reduces the interaction with
FT PDCD6IP and ANXA7.
FT MUTAGEN 60 60 F->A: Abolishes the interaction with
FT PDCD6IP, ANXA7 and ANXA11.
FT MUTAGEN 91 91 Y->A: Abolishes the interaction with
FT PDCD6IP, ANXA7 and ANXA11.
FT MUTAGEN 95 95 W->A: Abolishes the interaction with
FT PDCD6IP, ANXA7 and ANXA11.
FT MUTAGEN 114 114 E->A: Loss of interaction with SEC31A and
FT PLSCR3, and loss of localization to the
FT endoplasmic reticulum; when associated
FT with A-47.
FT MUTAGEN 122 122 F->A: Increases interaction with PDCD6IP
FT and ANXA7. Impairs interaction with
FT ANXA11. Augments stauroporine-induced
FT cell death.
FT MUTAGEN 122 122 F->G: Increases interaction with PDCD6IP.
FT Impairs interaction with ANXA11.
FT MUTAGEN 122 122 F->S: Increases interaction with PDCD6IP.
FT Impairs interaction with ANAX7 and
FT ANXA11.
FT MUTAGEN 122 122 F->W: Impairs interaction with ANXA11.
FT MUTAGEN 180 180 Y->A: Abolishes the interaction with
FT PDCD6IP, TSG101, ANXA7 and ANXA11.
FT HELIX 26 35
FT STRAND 36 40
FT STRAND 41 43
FT HELIX 45 51
FT STRAND 55 58
FT HELIX 62 72
FT STRAND 74 80
FT HELIX 82 102
FT STRAND 107 110
FT HELIX 112 121
FT HELIX 128 138
FT STRAND 143 147
FT HELIX 148 168
FT STRAND 172 174
FT HELIX 180 188
SQ SEQUENCE 191 AA; 21868 MW; D0B5944CF3C696AD CRC64;
MAAYSYRPGP GAGPGPAAGA ALPDQSFLWN VFQRVDKDRS GVISDTELQQ ALSNGTWTPF
NPVTVRSIIS MFDRENKAGV NFSEFTGVWK YITDWQNVFR TYDRDNSGMI DKNELKQALS
GFGYRLSDQF HDILIRKFDR QGRGQIAFDD FIQGCIVLQR LTDIFRRYDT DQDGWIQVSY
EQYLSMVFSI V
//
ID PDCD6_HUMAN Reviewed; 191 AA.
AC O75340; B2RD16; E7ESR3; Q2YDC2; Q5TZS0;
DT 11-JAN-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1998, sequence version 1.
DT 22-JAN-2014, entry version 130.
DE RecName: Full=Programmed cell death protein 6;
DE AltName: Full=Apoptosis-linked gene 2 protein;
DE AltName: Full=Probable calcium-binding protein ALG-2;
GN Name=PDCD6; Synonyms=ALG2;
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).
RA Ganjei J.K., D'Adamio L.;
RL Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RA Urcelay E., Ibarreta D., Parrilla R., Ayuso M.S.;
RL Submitted (MAY-1996) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Cerebellum;
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 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3).
RC TISSUE=Colon, Ovary, and Placenta;
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 [8]
RP INTERACTION WITH PEF1.
RX PubMed=11278427; DOI=10.1074/jbc.M008649200;
RA Kitaura Y., Matsumoto S., Satoh H., Hitomi K., Maki M.;
RT "Peflin and ALG-2, members of the penta-EF-hand protein family, form a
RT heterodimer that dissociates in a Ca2+-dependent manner.";
RL J. Biol. Chem. 276:14053-14058(2001).
RN [9]
RP INTERACTION WITH PEF1.
RX PubMed=11883899; DOI=10.1006/abbi.2001.2736;
RA Kitaura Y., Satoh H., Takahashi H., Shibata H., Maki M.;
RT "Both ALG-2 and peflin, penta-EF-hand (PEF) proteins, are stabilized
RT by dimerization through their fifth EF-hand regions.";
RL Arch. Biochem. Biophys. 399:12-18(2002).
RN [10]
RP INTERACTION WITH ANXA11.
RX PubMed=11883939; DOI=10.1006/bbrc.2002.6600;
RA Satoh H., Shibata H., Nakano Y., Kitaura Y., Maki M.;
RT "ALG-2 interacts with the amino-terminal domain of annexin XI in a
RT Ca(2+)-dependent manner.";
RL Biochem. Biophys. Res. Commun. 291:1166-1172(2002).
RN [11]
RP FUNCTION, AND INTERACTION WITH DAPK1.
RX PubMed=16132846; DOI=10.1007/s10529-005-7869-x;
RA Lee J.H., Rho S.B., Chun T.;
RT "Programmed cell death 6 (PDCD6) protein interacts with death-
RT associated protein kinase 1 (DAPk1): additive effect on apoptosis via
RT caspase-3 dependent pathway.";
RL Biotechnol. Lett. 27:1011-1015(2005).
RN [12]
RP INTERACTION WITH RBM22.
RX PubMed=17045351; DOI=10.1016/j.bbamcr.2006.09.003;
RA Montaville P., Dai Y., Cheung C.Y., Giller K., Becker S., Michalak M.,
RA Webb S.E., Miller A.L., Krebs J.;
RT "Nuclear translocation of the calcium-binding protein ALG-2 induced by
RT the RNA-binding protein RBM22.";
RL Biochim. Biophys. Acta 1763:1335-1343(2006).
RN [13]
RP INTERACTION WITH SEC31A AND PDCD6IP, MUTAGENESIS OF GLU-47 AND
RP GLU-114, AND SUBCELLULAR LOCATION.
RX PubMed=16957052; DOI=10.1091/mbc.E06-05-0444;
RA Yamasaki A., Tani K., Yamamoto A., Kitamura N., Komada M.;
RT "The Ca2+-binding protein ALG-2 is recruited to endoplasmic reticulum
RT exit sites by Sec31A and stabilizes the localization of Sec31A.";
RL Mol. Biol. Cell 17:4876-4887(2006).
RN [14]
RP FUNCTION, AND INTERACTION WITH WITH SHISA5.
RX PubMed=17889823; DOI=10.1016/j.abb.2007.07.028;
RA Draeby I., Woods Y.L., la Cour J.M., Mollerup J., Bourdon J.C.,
RA Berchtold M.W.;
RT "The calcium binding protein ALG-2 binds and stabilizes Scotin, a p53-
RT inducible gene product localized at the endoplasmic reticulum
RT membrane.";
RL Arch. Biochem. Biophys. 467:87-94(2007).
RN [15]
RP INTERACTION WITH PLSCR3; PLSCR4; PDCD6IP; ANXA7; ANXA11; SEC31A AND
RP TSG101, AND MUTAGENESIS OF GLU-47; TRP-57; PHE-60; TYR-91; TRP-95;
RP GLU-114 AND TYR-180.
RX PubMed=18256029; DOI=10.1074/jbc.M800717200;
RA Shibata H., Suzuki H., Kakiuchi T., Inuzuka T., Yoshida H., Mizuno T.,
RA Maki M.;
RT "Identification of Alix-type and non-Alix-type ALG-2-binding sites in
RT human phospholipid scramblase 3: differential binding to an
RT alternatively spliced isoform and amino acid-substituted mutants.";
RL J. Biol. Chem. 283:9623-9632(2008).
RN [16]
RP FUNCTION.
RX PubMed=19520058; DOI=10.1016/j.bbrc.2009.06.015;
RA Okumura M., Ichioka F., Kobayashi R., Suzuki H., Yoshida H.,
RA Shibata H., Maki M.;
RT "Penta-EF-hand protein ALG-2 functions as a Ca2+-dependent adaptor
RT that bridges Alix and TSG101.";
RL Biochem. Biophys. Res. Commun. 386:237-241(2009).
RN [17]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH MCOLN1.
RX PubMed=19864416; DOI=10.1074/jbc.M109.047241;
RA Vergarajauregui S., Martina J.A., Puertollano R.;
RT "Identification of the penta-EF-hand protein ALG-2 as a Ca2+-dependent
RT interactor of mucolipin-1.";
RL J. Biol. Chem. 284:36357-36366(2009).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [19]
RP SUBCELLULAR LOCATION.
RX PubMed=21122810; DOI=10.1016/j.bbamcr.2010.11.010;
RA Janowicz A., Michalak M., Krebs J.;
RT "Stress induced subcellular distribution of ALG-2, RBM22 and hSlu7.";
RL Biochim. Biophys. Acta 1813:1045-1049(2011).
RN [20]
RP FUNCTION, AND INTERACTION WITH KDR.
RX PubMed=21893193; DOI=10.1016/j.cellsig.2011.08.013;
RA Rho S.B., Song Y.J., Lim M.C., Lee S.H., Kim B.R., Park S.Y.;
RT "Programmed cell death 6 (PDCD6) inhibits angiogenesis through
RT PI3K/mTOR/p70S6K pathway by interacting of VEGFR-2.";
RL Cell. Signal. 24:131-139(2012).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 24-191 IN COMPLEXES WITH
RP CALCIUM; ZINC AND PDCD6IP, SUBUNIT, AND INTERACTION WITH PDCD6IP.
RX PubMed=18940611; DOI=10.1016/j.str.2008.07.012;
RA Suzuki H., Kawasaki M., Inuzuka T., Okumura M., Kakiuchi T.,
RA Shibata H., Wakatsuki S., Maki M.;
RT "Structural basis for Ca2+ -dependent formation of ALG-2/Alix peptide
RT complex: Ca2+/EF3-driven arginine switch mechanism.";
RL Structure 16:1562-1573(2008).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 24-191, INTERACTION WITH
RP PDCD6IP; TSG101; ANXA7 AND ANXA11, AND MUTAGENESIS OF PHE-122.
RX PubMed=20691033; DOI=10.1186/1472-6807-10-25;
RA Inuzuka T., Suzuki H., Kawasaki M., Shibata H., Wakatsuki S., Maki M.;
RT "Molecular basis for defect in Alix-binding by alternatively spliced
RT isoform of ALG-2 (ALG-2DeltaGF122) and structural roles of F122 in
RT target recognition.";
RL BMC Struct. Biol. 10:25-25(2010).
RN [23]
RP VARIANT [LARGE SCALE ANALYSIS] CYS-123.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Calcium-binding protein required for T-cell receptor-,
CC Fas-, and glucocorticoid-induced cell death. May mediate Ca(2+)-
CC regulated signals along the death pathway (By similarity).
CC Calcium-dependent adapter necessary for the association between
CC PDCD6IP and TSG101. Interaction with DAPK1 can accelerate
CC apoptotic cell death by increasing caspase-3 activity. May inhibit
CC KDR/VEGFR2-dependent angiogenesis; the function involves
CC inhibition of VEGF-induced phosphoprylation of the Akt signaling
CC pathway. Seems to play a role in the regulation of the
CC distribution and function of MCOLN1 in the endosomal pathway.
CC Isoform 2 has a lower Ca(2+) affinity than isoform 1. Isoform 1
CC and, to a lesser extend, isoform 2, can stabilize SHISA5.
CC -!- SUBUNIT: Isoform 1 and isoform 2 self-associate; probably forming
CC homodimers. Interacts with SHISA5, PEF1, RBM22, PLSCR4, ANXA7,
CC TSG101 and DAPK1. Interacts with PDCD6IP, SEC31A, ANXA11 (via N-
CC terminus), PLSCR3 (via N-terminus) and MCOLN1; the interactions
CC are calcium-dependent. Isoform 2 does not interact with SHISA5,
CC PDCD6IP, TSG101, ANXA7 and ANXA11.
CC -!- INTERACTION:
CC P53355:DAPK1; NbExp=3; IntAct=EBI-352915, EBI-358616;
CC P35968:KDR; NbExp=4; IntAct=EBI-352915, EBI-1005487;
CC Q8WUM4:PDCD6IP; NbExp=5; IntAct=EBI-352915, EBI-310624;
CC Q9NRY6:PLSCR3; NbExp=9; IntAct=EBI-352915, EBI-750734;
CC Q9H3S7:PTPN23; NbExp=3; IntAct=EBI-352915, EBI-724478;
CC O94979:SEC31A; NbExp=6; IntAct=EBI-352915, EBI-1767898;
CC -!- SUBCELLULAR LOCATION: Nucleus membrane; Peripheral membrane
CC protein. Endoplasmic reticulum membrane; Peripheral membrane
CC protein. Nucleus. Endosome. Note=Interaction with RBM22 induces
CC relocalization from the cytoplasm to the nucleus. Translocated
CC from the cytoplasm to the nucleus after heat shock cell treatment.
CC Accumulates in cytoplasmic vesicle-like organelles after heat
CC shock treatment, which may represent stress granules.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=O75340-1; Sequence=Displayed;
CC Name=2; Synonyms=ALG-2(delta)GF122;
CC IsoId=O75340-2; Sequence=VSP_045113;
CC Name=3;
CC IsoId=O75340-3; Sequence=VSP_045542;
CC Note=No experimental confirmation available;
CC -!- SIMILARITY: Contains 5 EF-hand domains.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/PDCD6ID43402ch5p15.html";
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DR EMBL; AF035606; AAC27697.1; -; mRNA.
DR EMBL; U58773; AAF14336.1; -; mRNA.
DR EMBL; AK315370; BAG37763.1; -; mRNA.
DR EMBL; BT020072; AAV38875.1; -; mRNA.
DR EMBL; AC010442; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC021087; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC118458; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471235; EAW50991.1; -; Genomic_DNA.
DR EMBL; BC012384; AAH12384.1; -; mRNA.
DR EMBL; BC106706; AAI06707.1; -; mRNA.
DR EMBL; BC110291; AAI10292.1; -; mRNA.
DR EMBL; CB991882; -; NOT_ANNOTATED_CDS; mRNA.
DR RefSeq; NP_001254485.1; NM_001267556.1.
DR RefSeq; NP_001254486.1; NM_001267557.1.
DR RefSeq; NP_001254487.1; NM_001267558.1.
DR RefSeq; NP_001254488.1; NM_001267559.1.
DR RefSeq; NP_037364.1; NM_013232.3.
DR UniGene; Hs.50823; -.
DR PDB; 2ZN8; X-ray; 2.70 A; A=2-191.
DR PDB; 2ZN9; X-ray; 2.40 A; A/B=20-191.
DR PDB; 2ZND; X-ray; 1.70 A; A=20-191.
DR PDB; 2ZNE; X-ray; 2.20 A; A/B=24-191.
DR PDB; 2ZRS; X-ray; 3.10 A; A/B/C/D/E/F/G/H=24-191.
DR PDB; 2ZRT; X-ray; 3.30 A; A/B/C/D/E/F/G/H=24-191.
DR PDB; 3AAJ; X-ray; 2.40 A; A/B=24-191.
DR PDB; 3AAK; X-ray; 2.70 A; A=20-191.
DR PDBsum; 2ZN8; -.
DR PDBsum; 2ZN9; -.
DR PDBsum; 2ZND; -.
DR PDBsum; 2ZNE; -.
DR PDBsum; 2ZRS; -.
DR PDBsum; 2ZRT; -.
DR PDBsum; 3AAJ; -.
DR PDBsum; 3AAK; -.
DR ProteinModelPortal; O75340; -.
DR SMR; O75340; 24-191.
DR DIP; DIP-33217N; -.
DR IntAct; O75340; 30.
DR MINT; MINT-5000341; -.
DR STRING; 9606.ENSP00000323816; -.
DR PhosphoSite; O75340; -.
DR PRIDE; O75340; -.
DR DNASU; 10016; -.
DR Ensembl; ENST00000264933; ENSP00000264933; ENSG00000249915.
DR Ensembl; ENST00000505221; ENSP00000422085; ENSG00000249915.
DR Ensembl; ENST00000507528; ENSP00000423815; ENSG00000249915.
DR GeneID; 10016; -.
DR KEGG; hsa:10016; -.
DR UCSC; uc031sik.1; human.
DR CTD; 10016; -.
DR GeneCards; GC05P000258; -.
DR HGNC; HGNC:8765; PDCD6.
DR MIM; 601057; gene.
DR neXtProt; NX_O75340; -.
DR PharmGKB; PA33115; -.
DR HOGENOM; HOG000231984; -.
DR HOVERGEN; HBG004492; -.
DR OMA; FLWNIFQ; -.
DR OrthoDB; EOG7RV9FM; -.
DR ChiTaRS; PDCD6; human.
DR EvolutionaryTrace; O75340; -.
DR GeneWiki; PDCD6; -.
DR GenomeRNAi; 10016; -.
DR NextBio; 37841; -.
DR PRO; PR:O75340; -.
DR ArrayExpress; O75340; -.
DR Bgee; O75340; -.
DR CleanEx; HS_ALG2; -.
DR CleanEx; HS_PDCD6; -.
DR Genevestigator; O75340; -.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005768; C:endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0031965; C:nuclear membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0060090; F:binding, bridging; IMP:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IEA:Ensembl.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0097190; P:apoptotic signaling pathway; TAS:ProtInc.
DR GO; GO:0033554; P:cellular response to stress; IDA:UniProtKB.
DR GO; GO:0006886; P:intracellular protein transport; IDA:UniProtKB.
DR GO; GO:0051898; P:negative regulation of protein kinase B signaling cascade; IDA:UniProtKB.
DR GO; GO:0032007; P:negative regulation of TOR signaling cascade; IDA:UniProtKB.
DR GO; GO:0030948; P:negative regulation of vascular endothelial growth factor receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IDA:UniProtKB.
DR GO; GO:0010595; P:positive regulation of endothelial cell migration; IDA:UniProtKB.
DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IDA:UniProtKB.
DR GO; GO:0051592; P:response to calcium ion; ISS:UniProtKB.
DR GO; GO:0036324; P:vascular endothelial growth factor receptor-2 signaling pathway; IDA:UniProtKB.
DR Gene3D; 1.10.238.10; -; 1.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR Pfam; PF13499; EF-hand_7; 1.
DR SMART; SM00054; EFh; 5.
DR PROSITE; PS00018; EF_HAND_1; 2.
DR PROSITE; PS50222; EF_HAND_2; 3.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Angiogenesis; Apoptosis; Calcium;
KW Complete proteome; Endoplasmic reticulum; Endosome; Membrane;
KW Metal-binding; Nucleus; Polymorphism; Reference proteome; Repeat.
FT CHAIN 1 191 Programmed cell death protein 6.
FT /FTId=PRO_0000073729.
FT DOMAIN 23 58 EF-hand 1.
FT DOMAIN 59 89 EF-hand 2.
FT DOMAIN 90 125 EF-hand 3.
FT DOMAIN 126 161 EF-hand 4.
FT DOMAIN 162 191 EF-hand 5.
FT CA_BIND 36 47 1.
FT CA_BIND 73 84 2 (Potential).
FT CA_BIND 103 114 3.
FT CA_BIND 169 181 4.
FT VAR_SEQ 70 191 Missing (in isoform 3).
FT /FTId=VSP_045542.
FT VAR_SEQ 121 122 Missing (in isoform 2).
FT /FTId=VSP_045113.
FT VARIANT 123 123 G -> C (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_035459.
FT MUTAGEN 47 47 E->A: Loss of interaction with SEC31A and
FT PLSCR3, and loss of localization to the
FT endoplasmic reticulum; when associated
FT with A-114.
FT MUTAGEN 57 57 W->A: Reduces the interaction with
FT PDCD6IP and ANXA7.
FT MUTAGEN 60 60 F->A: Abolishes the interaction with
FT PDCD6IP, ANXA7 and ANXA11.
FT MUTAGEN 91 91 Y->A: Abolishes the interaction with
FT PDCD6IP, ANXA7 and ANXA11.
FT MUTAGEN 95 95 W->A: Abolishes the interaction with
FT PDCD6IP, ANXA7 and ANXA11.
FT MUTAGEN 114 114 E->A: Loss of interaction with SEC31A and
FT PLSCR3, and loss of localization to the
FT endoplasmic reticulum; when associated
FT with A-47.
FT MUTAGEN 122 122 F->A: Increases interaction with PDCD6IP
FT and ANXA7. Impairs interaction with
FT ANXA11. Augments stauroporine-induced
FT cell death.
FT MUTAGEN 122 122 F->G: Increases interaction with PDCD6IP.
FT Impairs interaction with ANXA11.
FT MUTAGEN 122 122 F->S: Increases interaction with PDCD6IP.
FT Impairs interaction with ANAX7 and
FT ANXA11.
FT MUTAGEN 122 122 F->W: Impairs interaction with ANXA11.
FT MUTAGEN 180 180 Y->A: Abolishes the interaction with
FT PDCD6IP, TSG101, ANXA7 and ANXA11.
FT HELIX 26 35
FT STRAND 36 40
FT STRAND 41 43
FT HELIX 45 51
FT STRAND 55 58
FT HELIX 62 72
FT STRAND 74 80
FT HELIX 82 102
FT STRAND 107 110
FT HELIX 112 121
FT HELIX 128 138
FT STRAND 143 147
FT HELIX 148 168
FT STRAND 172 174
FT HELIX 180 188
SQ SEQUENCE 191 AA; 21868 MW; D0B5944CF3C696AD CRC64;
MAAYSYRPGP GAGPGPAAGA ALPDQSFLWN VFQRVDKDRS GVISDTELQQ ALSNGTWTPF
NPVTVRSIIS MFDRENKAGV NFSEFTGVWK YITDWQNVFR TYDRDNSGMI DKNELKQALS
GFGYRLSDQF HDILIRKFDR QGRGQIAFDD FIQGCIVLQR LTDIFRRYDT DQDGWIQVSY
EQYLSMVFSI V
//
MIM
601057
*RECORD*
*FIELD* NO
601057
*FIELD* TI
*601057 PROGRAMMED CELL DEATH 6; PDCD6
;;APOPTOSIS-LINKED GENE 2; ALG2
*FIELD* TX
read moreCLONING
The normal development of multicellular organisms is dependent on the
removal of 'unwanted' cells by a genetically controlled process termed
programmed cell death (PCD) that is typically mediated by apoptosis.
Dysregulation of this process contributes to or is suspected of
contributing to the pathogenesis of several diseases, including
neurodegenerative disorders (see 253300), cancer (see 151430),
autoimmune disease (see FAS; 134637), congenital malformations (see
185900), and immunodeficiency. Vito et al. (1996) designed a method to
select genes involved in apoptosis, using as a model PCD induced in a
mouse T-cell hybridoma by T-cell receptor cross-linking. The selection
system, which they named 'death trap,' is based on the assumption that a
transfected cDNA library constructed in the mammalian expression vector
pLTP should protect some recipient cells from death. Such inhibition may
depend on inactivation of apoptotic genes by either antisense RNA or
dominant-negative mutants or on overexpression of proteins with
antiapoptotic activity. Using this system, they isolated 6 cDNA clones,
designated apoptosis-linked genes (Alg1 to Alg6), that were able to
inhibit PCR-induced cell death in a transient transfection assay. Vito
et al. (1996) found that a 435-bp mouse Alg2 cDNA identified a single
1.3-kb transcript in mouse T-cell hybridoma cells and in all adult mouse
tissues analyzed. The thymus and liver showed the most expression,
whereas the testis and skeletal muscles showed the least. The
full-length Alg2 cDNA has an open reading frame predicted to encode a
protein of 191 amino acids.
GENE FUNCTION
Vito et al. (1996) showed that mouse Alg2 is a Ca(2+)-binding protein
required for T-cell receptor-, Fas-, and glucocorticoid-induced cell
death.
Using immunoblot analysis, Jung et al. (2001) showed that ALG2 is
expressed as a 22-kD protein before FAS activation and thereafter as a
19-kD protein, probably due to N-terminal cleavage. Confocal microscopy
and immunoprecipitation analysis demonstrated that ALG2 translocates
from the cytoplasmic membrane to the cytosol during FAS-induced
apoptosis and then dissociates from FAS after activation. Yeast 2-hybrid
and GST pull-down analyses confirmed that ALG2 interacts with FAS.
Kitaura et al. (2001) found that ALG2 coimmunoprecipitated with peflin
(PEF1; 610033) from Jurkat human T cells and from transfected HEK293
cells. Peflin dissociated from ALG2 in the presence of Ca(2+), and the
N-terminal hydrophobic domain of peflin was not essential for
heterodimerization. Peflin and ALG2 colocalized in the cytoplasm, but
ALG2 was also detected in nuclei, as revealed by immunofluorescence
staining and subcellular fractionation. Peflin was recovered in the
cytosolic fraction in the absence of Ca(2+) and in the
membrane/cytoskeletal fraction in the presence of Ca(2+). Kitaura et al.
(2001) concluded that peflin may modulate the function of ALG2 in Ca(2+)
signaling.
ANIMAL MODEL
Jang et al. (2002) generated viable and fertile mice deficient in Alg2
by gene targeting. The mice were developmentally and immunologically
normal. Analysis of apoptotic responses demonstrated that the Alg2
deficiency resulted in no block of apoptosis induced by TCR, FAS, or
dexamethasone signals. Jang et al. (2002) concluded that ALG2 is
physiologically dispensable in these signaling pathways and that other
functionally redundant proteins might exist in mammalian cells.
*FIELD* RF
1. Jang, I. K.; Hu, R.; Lacana, E.; D'Adamio, L.; Gu, H.: Apoptosis-linked
gene 2-deficient mice exhibit normal T-cell development and function. Molec.
Cell. Biol. 22: 4094-4100, 2002.
2. Jung, Y.-S.; Kim, K.-S.; Kim, K. D.; Lim, J.-S.; Kim, J.-W.; Kim,
E.: Apoptosis-linked gene 2 binds to the death domain of Fas and
dissociates from Fas during Fas-mediated apoptosis in Jurkat cells. Biochem.
Biophys. Res. Commun. 288: 420-426, 2001.
3. Kitaura, Y.; Matsumoto, S.; Satoh, H.; Hitomi, K.; Maki, M.: Peflin
and ALG-2, members of the penta-EF-hand protein family, form a heterodimer
that dissociates in a Ca(2+)-dependent manner. J. Biol. Chem. 276:
14053-14058, 2001.
4. Vito, P.; Lacana, E.; D'Adamio, L.: Interfering with apoptosis:
Ca(2+)-binding protein ALG-2 and Alzheimer's disease gene ALG-3. Science 271:
521-524, 1996.
*FIELD* CN
Patricia A. Hartz - updated: 04/07/2006
Paul J. Converse - updated: 6/21/2002
*FIELD* CD
Victor A. McKusick: 2/10/1996
*FIELD* ED
mgross: 04/07/2006
carol: 2/19/2004
mgross: 6/21/2002
carol: 7/18/2001
alopez: 12/14/1999
dkim: 9/11/1998
mark: 2/10/1996
*RECORD*
*FIELD* NO
601057
*FIELD* TI
*601057 PROGRAMMED CELL DEATH 6; PDCD6
;;APOPTOSIS-LINKED GENE 2; ALG2
*FIELD* TX
read moreCLONING
The normal development of multicellular organisms is dependent on the
removal of 'unwanted' cells by a genetically controlled process termed
programmed cell death (PCD) that is typically mediated by apoptosis.
Dysregulation of this process contributes to or is suspected of
contributing to the pathogenesis of several diseases, including
neurodegenerative disorders (see 253300), cancer (see 151430),
autoimmune disease (see FAS; 134637), congenital malformations (see
185900), and immunodeficiency. Vito et al. (1996) designed a method to
select genes involved in apoptosis, using as a model PCD induced in a
mouse T-cell hybridoma by T-cell receptor cross-linking. The selection
system, which they named 'death trap,' is based on the assumption that a
transfected cDNA library constructed in the mammalian expression vector
pLTP should protect some recipient cells from death. Such inhibition may
depend on inactivation of apoptotic genes by either antisense RNA or
dominant-negative mutants or on overexpression of proteins with
antiapoptotic activity. Using this system, they isolated 6 cDNA clones,
designated apoptosis-linked genes (Alg1 to Alg6), that were able to
inhibit PCR-induced cell death in a transient transfection assay. Vito
et al. (1996) found that a 435-bp mouse Alg2 cDNA identified a single
1.3-kb transcript in mouse T-cell hybridoma cells and in all adult mouse
tissues analyzed. The thymus and liver showed the most expression,
whereas the testis and skeletal muscles showed the least. The
full-length Alg2 cDNA has an open reading frame predicted to encode a
protein of 191 amino acids.
GENE FUNCTION
Vito et al. (1996) showed that mouse Alg2 is a Ca(2+)-binding protein
required for T-cell receptor-, Fas-, and glucocorticoid-induced cell
death.
Using immunoblot analysis, Jung et al. (2001) showed that ALG2 is
expressed as a 22-kD protein before FAS activation and thereafter as a
19-kD protein, probably due to N-terminal cleavage. Confocal microscopy
and immunoprecipitation analysis demonstrated that ALG2 translocates
from the cytoplasmic membrane to the cytosol during FAS-induced
apoptosis and then dissociates from FAS after activation. Yeast 2-hybrid
and GST pull-down analyses confirmed that ALG2 interacts with FAS.
Kitaura et al. (2001) found that ALG2 coimmunoprecipitated with peflin
(PEF1; 610033) from Jurkat human T cells and from transfected HEK293
cells. Peflin dissociated from ALG2 in the presence of Ca(2+), and the
N-terminal hydrophobic domain of peflin was not essential for
heterodimerization. Peflin and ALG2 colocalized in the cytoplasm, but
ALG2 was also detected in nuclei, as revealed by immunofluorescence
staining and subcellular fractionation. Peflin was recovered in the
cytosolic fraction in the absence of Ca(2+) and in the
membrane/cytoskeletal fraction in the presence of Ca(2+). Kitaura et al.
(2001) concluded that peflin may modulate the function of ALG2 in Ca(2+)
signaling.
ANIMAL MODEL
Jang et al. (2002) generated viable and fertile mice deficient in Alg2
by gene targeting. The mice were developmentally and immunologically
normal. Analysis of apoptotic responses demonstrated that the Alg2
deficiency resulted in no block of apoptosis induced by TCR, FAS, or
dexamethasone signals. Jang et al. (2002) concluded that ALG2 is
physiologically dispensable in these signaling pathways and that other
functionally redundant proteins might exist in mammalian cells.
*FIELD* RF
1. Jang, I. K.; Hu, R.; Lacana, E.; D'Adamio, L.; Gu, H.: Apoptosis-linked
gene 2-deficient mice exhibit normal T-cell development and function. Molec.
Cell. Biol. 22: 4094-4100, 2002.
2. Jung, Y.-S.; Kim, K.-S.; Kim, K. D.; Lim, J.-S.; Kim, J.-W.; Kim,
E.: Apoptosis-linked gene 2 binds to the death domain of Fas and
dissociates from Fas during Fas-mediated apoptosis in Jurkat cells. Biochem.
Biophys. Res. Commun. 288: 420-426, 2001.
3. Kitaura, Y.; Matsumoto, S.; Satoh, H.; Hitomi, K.; Maki, M.: Peflin
and ALG-2, members of the penta-EF-hand protein family, form a heterodimer
that dissociates in a Ca(2+)-dependent manner. J. Biol. Chem. 276:
14053-14058, 2001.
4. Vito, P.; Lacana, E.; D'Adamio, L.: Interfering with apoptosis:
Ca(2+)-binding protein ALG-2 and Alzheimer's disease gene ALG-3. Science 271:
521-524, 1996.
*FIELD* CN
Patricia A. Hartz - updated: 04/07/2006
Paul J. Converse - updated: 6/21/2002
*FIELD* CD
Victor A. McKusick: 2/10/1996
*FIELD* ED
mgross: 04/07/2006
carol: 2/19/2004
mgross: 6/21/2002
carol: 7/18/2001
alopez: 12/14/1999
dkim: 9/11/1998
mark: 2/10/1996