Full text data of TOLLIP
TOLLIP
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Toll-interacting protein
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Toll-interacting protein
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00100154
IPI00100154 Toll-interacting protein interleukin-1 receptor complex, interleukin-18 receptor complex, protein binding, signal transducer activity, Toll binding, cell-cell signaling, immune cell activation, inflammatory response, intracellular signaling cascade, phosphorylation soluble 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 n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00100154 Toll-interacting protein interleukin-1 receptor complex, interleukin-18 receptor complex, protein binding, signal transducer activity, Toll binding, cell-cell signaling, immune cell activation, inflammatory response, intracellular signaling cascade, phosphorylation soluble 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 n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
Q9H0E2
ID TOLIP_HUMAN Reviewed; 274 AA.
AC Q9H0E2; Q9H9E6; Q9UJ69;
DT 27-MAR-2002, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAR-2001, sequence version 1.
DT 22-JAN-2014, entry version 117.
DE RecName: Full=Toll-interacting protein;
GN Name=TOLLIP;
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].
RX PubMed=10854325; DOI=10.1038/35014038;
RA Burns K., Clatworthy J., Martin L., Martinon F., Plumpton C.,
RA Maschera B., Lewis A., Ray K., Tschopp J., Volpe F.;
RT "Tollip, a new component of the IL-1R1 pathway, links IRAK to the IL-1
RT receptor.";
RL Nat. Cell Biol. 2:346-351(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=11230166; DOI=10.1101/gr.GR1547R;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H.,
RA Lauber J., Duesterhoeft A., Beyer A., Koehrer K., Strack N.,
RA Mewes H.-W., Ottenwaelder B., Obermaier B., Tampe J., Heubner D.,
RA Wambutt R., Korn B., Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and
RT analysis of 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Eye, 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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 34-274.
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 [5]
RP INTERACTION WITH TLR2 AND TLR4, AND FUNCTION.
RX PubMed=11751856; DOI=10.1074/jbc.M109537200;
RA Zhang G., Ghosh S.;
RT "Negative regulation of Toll-like receptor-mediated signaling by
RT Tollip.";
RL J. Biol. Chem. 277:7059-7065(2002).
RN [6]
RP INTERACTION WITH TOM1L2.
RX PubMed=16412388; DOI=10.1016/j.bbrc.2005.12.156;
RA Katoh Y., Imakagura H., Futatsumori M., Nakayama K.;
RT "Recruitment of clathrin onto endosomes by the Tom1-Tollip complex.";
RL Biochem. Biophys. Res. Commun. 341:143-149(2006).
RN [7]
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 [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [9]
RP STRUCTURE BY NMR OF 229-274.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of CUE domain in the C-terminal of human Toll-
RT interacting protein (TOLLIP).";
RL Submitted (NOV-2004) to the PDB data bank.
CC -!- FUNCTION: Component of the signaling pathway of IL-1 and Toll-like
CC receptors. Inhibits cell activation by microbial products.
CC Recruits IRAK1 to the IL-1 receptor complex. Inhibits IRAK1
CC phosphorylation and kinase activity.
CC -!- SUBUNIT: Oligomerizes. Binds to TLR2 and the TLR4-MD2 complex via
CC its C-terminus. Exists as complex with IRAK1 in unstimulated
CC cells. Upon IL-1 signaling, Tollip binds to the activated IL-1
CC receptor complex containing IL-1RI, IL-1RacP and the adapter
CC protein MyD88, where it interacts with the TIR domain of IL-1RacP.
CC MyD88 then triggers IRAK1 autophosphorylation, which in turn leads
CC to the dissociation of IRAK1 from Tollip and IL-1RAcP. Interacts
CC with TOM1L2.
CC -!- INTERACTION:
CC Q05048:CSTF1; NbExp=2; IntAct=EBI-74615, EBI-1789619;
CC Q15038:DAZAP2; NbExp=3; IntAct=EBI-74615, EBI-724310;
CC Q86Y13:DZIP3; NbExp=2; IntAct=EBI-74615, EBI-948630;
CC P19525:EIF2AK2; NbExp=2; IntAct=EBI-74615, EBI-640775;
CC O43187:IRAK2; NbExp=2; IntAct=EBI-74615, EBI-447733;
CC Q86TG7:PEG10; NbExp=2; IntAct=EBI-74615, EBI-2858265;
CC O75674:TOM1L1; NbExp=3; IntAct=EBI-74615, EBI-712991;
CC Q96S55:WRNIP1; NbExp=2; IntAct=EBI-74615, EBI-2513471;
CC -!- SUBCELLULAR LOCATION: Cytoplasm (Probable).
CC -!- PTM: Phosphorylated by IRAK1 upon stimulation by IL-1 or microbial
CC products.
CC -!- SIMILARITY: Belongs to the tollip family.
CC -!- SIMILARITY: Contains 1 C2 domain.
CC -!- SIMILARITY: Contains 1 CUE domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB14283.1; Type=Erroneous initiation;
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AJ242972; CAB58118.1; -; mRNA.
DR EMBL; AL136835; CAB66769.1; -; mRNA.
DR EMBL; BC004420; AAH04420.1; -; mRNA.
DR EMBL; BC012057; AAH12057.1; -; mRNA.
DR EMBL; BC018272; AAH18272.1; -; mRNA.
DR EMBL; AK022871; BAB14283.1; ALT_INIT; mRNA.
DR RefSeq; NP_061882.2; NM_019009.3.
DR UniGene; Hs.368527; -.
DR PDB; 1WGL; NMR; -; A=229-274.
DR PDBsum; 1WGL; -.
DR ProteinModelPortal; Q9H0E2; -.
DR SMR; Q9H0E2; 231-274.
DR IntAct; Q9H0E2; 43.
DR MINT; MINT-4539075; -.
DR STRING; 9606.ENSP00000314733; -.
DR PhosphoSite; Q9H0E2; -.
DR DMDM; 20140803; -.
DR PaxDb; Q9H0E2; -.
DR PRIDE; Q9H0E2; -.
DR DNASU; 54472; -.
DR Ensembl; ENST00000317204; ENSP00000314733; ENSG00000078902.
DR GeneID; 54472; -.
DR KEGG; hsa:54472; -.
DR UCSC; uc001ltd.3; human.
DR CTD; 54472; -.
DR GeneCards; GC11M001295; -.
DR HGNC; HGNC:16476; TOLLIP.
DR HPA; HPA038621; -.
DR HPA; HPA038622; -.
DR MIM; 606277; gene.
DR neXtProt; NX_Q9H0E2; -.
DR PharmGKB; PA134876213; -.
DR eggNOG; NOG85357; -.
DR HOGENOM; HOG000293427; -.
DR HOVERGEN; HBG054213; -.
DR KO; K05402; -.
DR OMA; HVTIPES; -.
DR PhylomeDB; Q9H0E2; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q9H0E2; -.
DR EvolutionaryTrace; Q9H0E2; -.
DR GeneWiki; TOLLIP; -.
DR GenomeRNAi; 54472; -.
DR NextBio; 56772; -.
DR PRO; PR:Q9H0E2; -.
DR ArrayExpress; Q9H0E2; -.
DR Bgee; Q9H0E2; -.
DR CleanEx; HS_TOLLIP; -.
DR Genevestigator; Q9H0E2; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0045323; C:interleukin-1 receptor complex; NAS:UniProtKB.
DR GO; GO:0045092; C:interleukin-18 receptor complex; NAS:UniProtKB.
DR GO; GO:0016604; C:nuclear body; IEA:Ensembl.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0004871; F:signal transducer activity; NAS:UniProtKB.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:0006954; P:inflammatory response; NAS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0035556; P:intracellular signal transduction; NAS:UniProtKB.
DR GO; GO:0045321; P:leukocyte activation; NAS:UniProtKB.
DR GO; GO:0016310; P:phosphorylation; IDA:UniProtKB.
DR GO; GO:0033235; P:positive regulation of protein sumoylation; IEA:Ensembl.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR003892; CUE.
DR InterPro; IPR009060; UBA-like.
DR Pfam; PF00168; C2; 1.
DR Pfam; PF02845; CUE; 1.
DR SMART; SM00239; C2; 1.
DR SMART; SM00546; CUE; 1.
DR SUPFAM; SSF46934; SSF46934; 1.
DR SUPFAM; SSF49562; SSF49562; 1.
DR PROSITE; PS50004; C2; FALSE_NEG.
DR PROSITE; PS51140; CUE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Cytoplasm; Immunity;
KW Inflammatory response; Innate immunity; Phosphoprotein; Polymorphism;
KW Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 274 Toll-interacting protein.
FT /FTId=PRO_0000072625.
FT DOMAIN 40 135 C2.
FT DOMAIN 229 272 CUE.
FT COMPBIAS 28 44 Gln-rich.
FT MOD_RES 2 2 N-acetylalanine.
FT VARIANT 222 222 A -> S (in dbSNP:rs5744015).
FT /FTId=VAR_034557.
FT CONFLICT 40 40 Missing (in Ref. 1; CAB58118).
FT CONFLICT 150 150 K -> E (in Ref. 3; BAB14283).
FT HELIX 231 240
FT STRAND 242 244
FT HELIX 246 253
FT TURN 254 258
FT HELIX 260 269
SQ SEQUENCE 274 AA; 30282 MW; 386E0F284D3837DA CRC64;
MATTVSTQRG PVYIGELPQD FLRITPTQQQ RQVQLDAQAA QQLQYGGAVG TVGRLNITVV
QAKLAKNYGM TRMDPYCRLR LGYAVYETPT AHNGAKNPRW NKVIHCTVPP GVDSFYLEIF
DERAFSMDDR IAWTHITIPE SLRQGKVEDK WYSLSGRQGD DKEGMINLVM SYALLPAAMV
MPPQPVVLMP TVYQQGVGYV PITGMPAVCS PGMVPVALPP AAVNAQPRCS EEDLKAIQDM
FPNMDQEVIR SVLEAQRGNK DAAINSLLQM GEEP
//
ID TOLIP_HUMAN Reviewed; 274 AA.
AC Q9H0E2; Q9H9E6; Q9UJ69;
DT 27-MAR-2002, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAR-2001, sequence version 1.
DT 22-JAN-2014, entry version 117.
DE RecName: Full=Toll-interacting protein;
GN Name=TOLLIP;
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].
RX PubMed=10854325; DOI=10.1038/35014038;
RA Burns K., Clatworthy J., Martin L., Martinon F., Plumpton C.,
RA Maschera B., Lewis A., Ray K., Tschopp J., Volpe F.;
RT "Tollip, a new component of the IL-1R1 pathway, links IRAK to the IL-1
RT receptor.";
RL Nat. Cell Biol. 2:346-351(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=11230166; DOI=10.1101/gr.GR1547R;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H.,
RA Lauber J., Duesterhoeft A., Beyer A., Koehrer K., Strack N.,
RA Mewes H.-W., Ottenwaelder B., Obermaier B., Tampe J., Heubner D.,
RA Wambutt R., Korn B., Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and
RT analysis of 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Eye, 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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 34-274.
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 [5]
RP INTERACTION WITH TLR2 AND TLR4, AND FUNCTION.
RX PubMed=11751856; DOI=10.1074/jbc.M109537200;
RA Zhang G., Ghosh S.;
RT "Negative regulation of Toll-like receptor-mediated signaling by
RT Tollip.";
RL J. Biol. Chem. 277:7059-7065(2002).
RN [6]
RP INTERACTION WITH TOM1L2.
RX PubMed=16412388; DOI=10.1016/j.bbrc.2005.12.156;
RA Katoh Y., Imakagura H., Futatsumori M., Nakayama K.;
RT "Recruitment of clathrin onto endosomes by the Tom1-Tollip complex.";
RL Biochem. Biophys. Res. Commun. 341:143-149(2006).
RN [7]
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 [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [9]
RP STRUCTURE BY NMR OF 229-274.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of CUE domain in the C-terminal of human Toll-
RT interacting protein (TOLLIP).";
RL Submitted (NOV-2004) to the PDB data bank.
CC -!- FUNCTION: Component of the signaling pathway of IL-1 and Toll-like
CC receptors. Inhibits cell activation by microbial products.
CC Recruits IRAK1 to the IL-1 receptor complex. Inhibits IRAK1
CC phosphorylation and kinase activity.
CC -!- SUBUNIT: Oligomerizes. Binds to TLR2 and the TLR4-MD2 complex via
CC its C-terminus. Exists as complex with IRAK1 in unstimulated
CC cells. Upon IL-1 signaling, Tollip binds to the activated IL-1
CC receptor complex containing IL-1RI, IL-1RacP and the adapter
CC protein MyD88, where it interacts with the TIR domain of IL-1RacP.
CC MyD88 then triggers IRAK1 autophosphorylation, which in turn leads
CC to the dissociation of IRAK1 from Tollip and IL-1RAcP. Interacts
CC with TOM1L2.
CC -!- INTERACTION:
CC Q05048:CSTF1; NbExp=2; IntAct=EBI-74615, EBI-1789619;
CC Q15038:DAZAP2; NbExp=3; IntAct=EBI-74615, EBI-724310;
CC Q86Y13:DZIP3; NbExp=2; IntAct=EBI-74615, EBI-948630;
CC P19525:EIF2AK2; NbExp=2; IntAct=EBI-74615, EBI-640775;
CC O43187:IRAK2; NbExp=2; IntAct=EBI-74615, EBI-447733;
CC Q86TG7:PEG10; NbExp=2; IntAct=EBI-74615, EBI-2858265;
CC O75674:TOM1L1; NbExp=3; IntAct=EBI-74615, EBI-712991;
CC Q96S55:WRNIP1; NbExp=2; IntAct=EBI-74615, EBI-2513471;
CC -!- SUBCELLULAR LOCATION: Cytoplasm (Probable).
CC -!- PTM: Phosphorylated by IRAK1 upon stimulation by IL-1 or microbial
CC products.
CC -!- SIMILARITY: Belongs to the tollip family.
CC -!- SIMILARITY: Contains 1 C2 domain.
CC -!- SIMILARITY: Contains 1 CUE domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB14283.1; Type=Erroneous initiation;
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AJ242972; CAB58118.1; -; mRNA.
DR EMBL; AL136835; CAB66769.1; -; mRNA.
DR EMBL; BC004420; AAH04420.1; -; mRNA.
DR EMBL; BC012057; AAH12057.1; -; mRNA.
DR EMBL; BC018272; AAH18272.1; -; mRNA.
DR EMBL; AK022871; BAB14283.1; ALT_INIT; mRNA.
DR RefSeq; NP_061882.2; NM_019009.3.
DR UniGene; Hs.368527; -.
DR PDB; 1WGL; NMR; -; A=229-274.
DR PDBsum; 1WGL; -.
DR ProteinModelPortal; Q9H0E2; -.
DR SMR; Q9H0E2; 231-274.
DR IntAct; Q9H0E2; 43.
DR MINT; MINT-4539075; -.
DR STRING; 9606.ENSP00000314733; -.
DR PhosphoSite; Q9H0E2; -.
DR DMDM; 20140803; -.
DR PaxDb; Q9H0E2; -.
DR PRIDE; Q9H0E2; -.
DR DNASU; 54472; -.
DR Ensembl; ENST00000317204; ENSP00000314733; ENSG00000078902.
DR GeneID; 54472; -.
DR KEGG; hsa:54472; -.
DR UCSC; uc001ltd.3; human.
DR CTD; 54472; -.
DR GeneCards; GC11M001295; -.
DR HGNC; HGNC:16476; TOLLIP.
DR HPA; HPA038621; -.
DR HPA; HPA038622; -.
DR MIM; 606277; gene.
DR neXtProt; NX_Q9H0E2; -.
DR PharmGKB; PA134876213; -.
DR eggNOG; NOG85357; -.
DR HOGENOM; HOG000293427; -.
DR HOVERGEN; HBG054213; -.
DR KO; K05402; -.
DR OMA; HVTIPES; -.
DR PhylomeDB; Q9H0E2; -.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q9H0E2; -.
DR EvolutionaryTrace; Q9H0E2; -.
DR GeneWiki; TOLLIP; -.
DR GenomeRNAi; 54472; -.
DR NextBio; 56772; -.
DR PRO; PR:Q9H0E2; -.
DR ArrayExpress; Q9H0E2; -.
DR Bgee; Q9H0E2; -.
DR CleanEx; HS_TOLLIP; -.
DR Genevestigator; Q9H0E2; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0045323; C:interleukin-1 receptor complex; NAS:UniProtKB.
DR GO; GO:0045092; C:interleukin-18 receptor complex; NAS:UniProtKB.
DR GO; GO:0016604; C:nuclear body; IEA:Ensembl.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0004871; F:signal transducer activity; NAS:UniProtKB.
DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR GO; GO:0006954; P:inflammatory response; NAS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0035556; P:intracellular signal transduction; NAS:UniProtKB.
DR GO; GO:0045321; P:leukocyte activation; NAS:UniProtKB.
DR GO; GO:0016310; P:phosphorylation; IDA:UniProtKB.
DR GO; GO:0033235; P:positive regulation of protein sumoylation; IEA:Ensembl.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR003892; CUE.
DR InterPro; IPR009060; UBA-like.
DR Pfam; PF00168; C2; 1.
DR Pfam; PF02845; CUE; 1.
DR SMART; SM00239; C2; 1.
DR SMART; SM00546; CUE; 1.
DR SUPFAM; SSF46934; SSF46934; 1.
DR SUPFAM; SSF49562; SSF49562; 1.
DR PROSITE; PS50004; C2; FALSE_NEG.
DR PROSITE; PS51140; CUE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Cytoplasm; Immunity;
KW Inflammatory response; Innate immunity; Phosphoprotein; Polymorphism;
KW Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 274 Toll-interacting protein.
FT /FTId=PRO_0000072625.
FT DOMAIN 40 135 C2.
FT DOMAIN 229 272 CUE.
FT COMPBIAS 28 44 Gln-rich.
FT MOD_RES 2 2 N-acetylalanine.
FT VARIANT 222 222 A -> S (in dbSNP:rs5744015).
FT /FTId=VAR_034557.
FT CONFLICT 40 40 Missing (in Ref. 1; CAB58118).
FT CONFLICT 150 150 K -> E (in Ref. 3; BAB14283).
FT HELIX 231 240
FT STRAND 242 244
FT HELIX 246 253
FT TURN 254 258
FT HELIX 260 269
SQ SEQUENCE 274 AA; 30282 MW; 386E0F284D3837DA CRC64;
MATTVSTQRG PVYIGELPQD FLRITPTQQQ RQVQLDAQAA QQLQYGGAVG TVGRLNITVV
QAKLAKNYGM TRMDPYCRLR LGYAVYETPT AHNGAKNPRW NKVIHCTVPP GVDSFYLEIF
DERAFSMDDR IAWTHITIPE SLRQGKVEDK WYSLSGRQGD DKEGMINLVM SYALLPAAMV
MPPQPVVLMP TVYQQGVGYV PITGMPAVCS PGMVPVALPP AAVNAQPRCS EEDLKAIQDM
FPNMDQEVIR SVLEAQRGNK DAAINSLLQM GEEP
//
MIM
606277
*RECORD*
*FIELD* NO
606277
*FIELD* TI
*606277 TOLL-INTERACTING PROTEIN; TOLLIP
*FIELD* TX
DESCRIPTION
TOLLIP is a ubiquitin-binding protein that interacts with several
read morecomponents of the Toll-like receptor (TLR; see 603030) signaling
cascade. It is an essential regulator of inflammatory signaling and is
involved in trafficking of interleukin-1 receptor (IL1R; 147810) and
turnover of IL1R-associated kinase (IRAK, or IRAK1; 300283) (summary by
Lo et al., 2009).
CLONING
The Toll/IL1R (TIR) domain is highly conserved in the cytoplasmic
regions of molecules associated with innate immunity, such as IL1R, IL1R
accessory protein (IL1RAP; 602626), and the TLRs. Using a yeast 2-hybrid
screen of a mouse embryonic library with the cytoplasmic tail of Il1rap
as bait, followed by database searching, Burns et al. (2000) obtained
cDNAs encoding mouse, worm, and human TOLLIP. The deduced 274-amino acid
human TOLLIP protein, which is 97% identical to the mouse sequence,
contains a type II C2 motif spanning residues 54 to 186. Northern blot
analysis revealed ubiquitous expression of a 3.8-kb Tollip transcript in
mouse tissues, with additional 2.1- and 1.1-kb transcripts in testis.
Immunoblot analysis showed expression of a 28-kD protein in numerous
mouse tissues.
Lo et al. (2009) stated that TOLLIP has an N-terminal TOM1
(604700)-binding domain (TBD) that mediates protein-protein
interactions, a C2 domain that targets TOLLIP to the endosome, and a
C-terminal CUE domain that binds monoubiquitin. Using computational and
PCR analyses, Lo et al. (2009) identified several alternate mouse and
human TOLLIP transcripts predicted to generate 5 protein isoforms
between the 2 species. The 4 human isoforms contain 205 to 274 amino
acids. Compared with the full-length isoform, 2 of the human proteins
lack the N-terminal TBD, and 1 lacks the C2 domain. A mouse-specific
isoform lacks the C-terminal CUE domain. EST database analysis suggested
that full-length human TOLLIP is ubiquitously expressed. Expression of
the other human variants appeared to be more restricted, with evidence
for enrichment in brain.
GENE STRUCTURE
Lo et al. (2009) determined that the TOLLIP gene contains 7 exons,
including an alternate first exon.
MAPPING
Lo et al. (2009) stated that the TOLLIP gene maps to chromosome 11. The
mouse gene maps to chromosome 7.
Gross (2013) mapped the TOLLIP gene to chromosome 11p15.5 based on an
alignment of the TOLLIP sequence (GenBank GENBANK AY730683) with the
genomic sequence (GRCh37).
GENE FUNCTION
By Western blot analysis of embryonic kidney cells, Burns et al. (2000)
confirmed the binding of TOLLIP to IL1RAP, to a complex of IL1RAP-IL1R1,
and to IL18R (604494). Immunoprecipitation and 2-hybrid analyses
indicated that cytosolic TOLLIP-IRAK1 complexes exist constitutively,
that TOLLIP rather than MYD88 (602170) recruits IRAK to the IL1R
complex, and that the association of TOLLIP with the N terminus of IRAK1
is lost after stimulation with IL1B (147720) and phosphorylation of IRAK
thr66. Burns et al. (2000) proposed that IL1B stimulation induces
aggregation of IL1Rs, recruitment of MYD88 followed by TOLLIP-IRAK
complexes, and the phosphorylation of IRAK by MYD88. This leads to the
dissociation of TOLLIP from IRAK, which can then transmit the
IL1-induced signals.
By immunoprecipitation analyses, Bulut et al. (2001) showed that TOLLIP
interacts with TLR2 (603028) and TLR4 (603030) and that overexpression
of TOLLIP inhibits nuclear factor kappa-B (NFKB; see 164011) activation
in response to lipopolysaccharide and IL1B, but not in response to tumor
necrosis factor-alpha (TNF; 191160).
Shah et al. (2012) found that knockdown of TOLLIP via short hairpin RNA
in human peripheral blood monocytes resulted in elevated levels of IL6
(147620) and TNF following stimulation with TLR ligands or Mycobacterium
tuberculosis (TB; see 607948) compared with controls. TOLLIP knockdown
in LPS-stimulated cells resulted in decreased IL10 (124092) expression.
Shah et al. (2012) concluded that TOLLIP has an antiinflammatory effect
on TLR signaling.
MOLECULAR GENETICS
- Associations Pending Confirmation
Shah et al. (2012) genotyped 9 haplotype-tagging SNPs in TOLLIP in 84
healthy volunteers and examined their associations with TOLLIP mRNA
expression in monocytes. They found that homozygosity for the minor T
allele of dbSNP rs3750920 was associated with increased TOLLIP mRNA
expression compared with CT heterozygotes and CC homozygotes.
Homozygosity for the minor G allele of dbSNP rs5743899 was associated
with decreased TOLLIP mRNA expression compared with AG heterozygotes and
AA homozygotes, and GG individuals produced higher levels of IL6 in
response to stimulation with TLR2 agonists or M. tuberculosis, but not
with LPS, a TLR4 agonist. IL10 levels were decreased in individuals
homozygous for the G allele of dbSNP rs5743899 after stimulation with
LPS. Using a candidate gene case-population study of 671 Vietnamese TB
patients and 760 cord blood controls, Shah et al. (2012) found that the
minor alleles of dbSNP rs3750920 and dbSNP rs5743899 were associated
with protection from and susceptibility to TB (607948), respectively (p
= 7.03 x 10(-16) and p = 6.97 x 10(-7), respectively). Shah et al.
(2012) concluded that regulation of the TLR pathway by TOLLIP is
critical in susceptibility to TB.
*FIELD* RF
1. Bulut, Y.; Faure, E.; Thomas, L.; Equils, O.; Arditi, M.: Cooperation
of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis
factor and Borrelia burgdorferi outer surface protein A lipoprotein:
role of Toll-interacting protein and IL-1 receptor signaling molecules
in Toll-like receptor 2 signaling. J. Immun. 167: 987-994, 2001.
2. Burns, K.; Clatworthy, J.; Martin, L.; Martinon, F.; Plumpton,
C.; Maschera, B.; Lewis, A.; Ray, K.; Tschopp, J.; Volpe, F.: Tollip,
a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nature
Cell Biol. 2: 346-351, 2000.
3. Gross, M. B.: Personal Communication. Baltimore, Md. 7/1/2013.
4. Lo, Y.-L. S.; Beckhouse, A. G.; Boulus, S. L.; Wells, C. A.: Diversification
of TOLLIP isoforms in mouse and man. Mammalian Genome 20: 305-314,
2009.
5. Shah, J. A.; Vary, J. C.; Chau, T. T. H.; Bang, N. D.; Yen, N.
T. B.; Farrar, J. J.; Dunstan, S. J.; Hawn, T. R.: Human TOLLIP regulates
TLR2 and TLR4 signaling and its polymorphisms are associated with
susceptibility to tuberculosis. J. Immun. 189: 1737-1746, 2012.
*FIELD* CN
Paul J. Converse - updated: 07/01/2013
Matthew B. Gross - updated: 7/1/2013
Matthew B. Gross - updated: 12/10/2009
Paul J. Converse - updated: 12/2/2009
*FIELD* CD
Paul J. Converse: 9/21/2001
*FIELD* ED
mgross: 07/01/2013
mgross: 7/1/2013
mgross: 12/10/2009
terry: 12/2/2009
alopez: 3/3/2008
mgross: 9/21/2001
*RECORD*
*FIELD* NO
606277
*FIELD* TI
*606277 TOLL-INTERACTING PROTEIN; TOLLIP
*FIELD* TX
DESCRIPTION
TOLLIP is a ubiquitin-binding protein that interacts with several
read morecomponents of the Toll-like receptor (TLR; see 603030) signaling
cascade. It is an essential regulator of inflammatory signaling and is
involved in trafficking of interleukin-1 receptor (IL1R; 147810) and
turnover of IL1R-associated kinase (IRAK, or IRAK1; 300283) (summary by
Lo et al., 2009).
CLONING
The Toll/IL1R (TIR) domain is highly conserved in the cytoplasmic
regions of molecules associated with innate immunity, such as IL1R, IL1R
accessory protein (IL1RAP; 602626), and the TLRs. Using a yeast 2-hybrid
screen of a mouse embryonic library with the cytoplasmic tail of Il1rap
as bait, followed by database searching, Burns et al. (2000) obtained
cDNAs encoding mouse, worm, and human TOLLIP. The deduced 274-amino acid
human TOLLIP protein, which is 97% identical to the mouse sequence,
contains a type II C2 motif spanning residues 54 to 186. Northern blot
analysis revealed ubiquitous expression of a 3.8-kb Tollip transcript in
mouse tissues, with additional 2.1- and 1.1-kb transcripts in testis.
Immunoblot analysis showed expression of a 28-kD protein in numerous
mouse tissues.
Lo et al. (2009) stated that TOLLIP has an N-terminal TOM1
(604700)-binding domain (TBD) that mediates protein-protein
interactions, a C2 domain that targets TOLLIP to the endosome, and a
C-terminal CUE domain that binds monoubiquitin. Using computational and
PCR analyses, Lo et al. (2009) identified several alternate mouse and
human TOLLIP transcripts predicted to generate 5 protein isoforms
between the 2 species. The 4 human isoforms contain 205 to 274 amino
acids. Compared with the full-length isoform, 2 of the human proteins
lack the N-terminal TBD, and 1 lacks the C2 domain. A mouse-specific
isoform lacks the C-terminal CUE domain. EST database analysis suggested
that full-length human TOLLIP is ubiquitously expressed. Expression of
the other human variants appeared to be more restricted, with evidence
for enrichment in brain.
GENE STRUCTURE
Lo et al. (2009) determined that the TOLLIP gene contains 7 exons,
including an alternate first exon.
MAPPING
Lo et al. (2009) stated that the TOLLIP gene maps to chromosome 11. The
mouse gene maps to chromosome 7.
Gross (2013) mapped the TOLLIP gene to chromosome 11p15.5 based on an
alignment of the TOLLIP sequence (GenBank GENBANK AY730683) with the
genomic sequence (GRCh37).
GENE FUNCTION
By Western blot analysis of embryonic kidney cells, Burns et al. (2000)
confirmed the binding of TOLLIP to IL1RAP, to a complex of IL1RAP-IL1R1,
and to IL18R (604494). Immunoprecipitation and 2-hybrid analyses
indicated that cytosolic TOLLIP-IRAK1 complexes exist constitutively,
that TOLLIP rather than MYD88 (602170) recruits IRAK to the IL1R
complex, and that the association of TOLLIP with the N terminus of IRAK1
is lost after stimulation with IL1B (147720) and phosphorylation of IRAK
thr66. Burns et al. (2000) proposed that IL1B stimulation induces
aggregation of IL1Rs, recruitment of MYD88 followed by TOLLIP-IRAK
complexes, and the phosphorylation of IRAK by MYD88. This leads to the
dissociation of TOLLIP from IRAK, which can then transmit the
IL1-induced signals.
By immunoprecipitation analyses, Bulut et al. (2001) showed that TOLLIP
interacts with TLR2 (603028) and TLR4 (603030) and that overexpression
of TOLLIP inhibits nuclear factor kappa-B (NFKB; see 164011) activation
in response to lipopolysaccharide and IL1B, but not in response to tumor
necrosis factor-alpha (TNF; 191160).
Shah et al. (2012) found that knockdown of TOLLIP via short hairpin RNA
in human peripheral blood monocytes resulted in elevated levels of IL6
(147620) and TNF following stimulation with TLR ligands or Mycobacterium
tuberculosis (TB; see 607948) compared with controls. TOLLIP knockdown
in LPS-stimulated cells resulted in decreased IL10 (124092) expression.
Shah et al. (2012) concluded that TOLLIP has an antiinflammatory effect
on TLR signaling.
MOLECULAR GENETICS
- Associations Pending Confirmation
Shah et al. (2012) genotyped 9 haplotype-tagging SNPs in TOLLIP in 84
healthy volunteers and examined their associations with TOLLIP mRNA
expression in monocytes. They found that homozygosity for the minor T
allele of dbSNP rs3750920 was associated with increased TOLLIP mRNA
expression compared with CT heterozygotes and CC homozygotes.
Homozygosity for the minor G allele of dbSNP rs5743899 was associated
with decreased TOLLIP mRNA expression compared with AG heterozygotes and
AA homozygotes, and GG individuals produced higher levels of IL6 in
response to stimulation with TLR2 agonists or M. tuberculosis, but not
with LPS, a TLR4 agonist. IL10 levels were decreased in individuals
homozygous for the G allele of dbSNP rs5743899 after stimulation with
LPS. Using a candidate gene case-population study of 671 Vietnamese TB
patients and 760 cord blood controls, Shah et al. (2012) found that the
minor alleles of dbSNP rs3750920 and dbSNP rs5743899 were associated
with protection from and susceptibility to TB (607948), respectively (p
= 7.03 x 10(-16) and p = 6.97 x 10(-7), respectively). Shah et al.
(2012) concluded that regulation of the TLR pathway by TOLLIP is
critical in susceptibility to TB.
*FIELD* RF
1. Bulut, Y.; Faure, E.; Thomas, L.; Equils, O.; Arditi, M.: Cooperation
of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis
factor and Borrelia burgdorferi outer surface protein A lipoprotein:
role of Toll-interacting protein and IL-1 receptor signaling molecules
in Toll-like receptor 2 signaling. J. Immun. 167: 987-994, 2001.
2. Burns, K.; Clatworthy, J.; Martin, L.; Martinon, F.; Plumpton,
C.; Maschera, B.; Lewis, A.; Ray, K.; Tschopp, J.; Volpe, F.: Tollip,
a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nature
Cell Biol. 2: 346-351, 2000.
3. Gross, M. B.: Personal Communication. Baltimore, Md. 7/1/2013.
4. Lo, Y.-L. S.; Beckhouse, A. G.; Boulus, S. L.; Wells, C. A.: Diversification
of TOLLIP isoforms in mouse and man. Mammalian Genome 20: 305-314,
2009.
5. Shah, J. A.; Vary, J. C.; Chau, T. T. H.; Bang, N. D.; Yen, N.
T. B.; Farrar, J. J.; Dunstan, S. J.; Hawn, T. R.: Human TOLLIP regulates
TLR2 and TLR4 signaling and its polymorphisms are associated with
susceptibility to tuberculosis. J. Immun. 189: 1737-1746, 2012.
*FIELD* CN
Paul J. Converse - updated: 07/01/2013
Matthew B. Gross - updated: 7/1/2013
Matthew B. Gross - updated: 12/10/2009
Paul J. Converse - updated: 12/2/2009
*FIELD* CD
Paul J. Converse: 9/21/2001
*FIELD* ED
mgross: 07/01/2013
mgross: 7/1/2013
mgross: 12/10/2009
terry: 12/2/2009
alopez: 3/3/2008
mgross: 9/21/2001