| Structural highlights
Function
CLUS_HUMAN Functions as extracellular chaperone that prevents aggregation of non native proteins (PubMed:11123922, PubMed:19535339). Prevents stress-induced aggregation of blood plasma proteins (PubMed:11123922, PubMed:12176985, PubMed:17260971, PubMed:19996109). Inhibits formation of amyloid fibrils by APP, APOC2, B2M, CALCA, CSN3, SNCA and aggregation-prone LYZ variants (in vitro) (PubMed:12047389, PubMed:17407782, PubMed:17412999). Does not require ATP (PubMed:11123922). Maintains partially unfolded proteins in a state appropriate for subsequent refolding by other chaperones, such as HSPA8/HSC70 (PubMed:11123922). Does not refold proteins by itself (PubMed:11123922). Binding to cell surface receptors triggers internalization of the chaperone-client complex and subsequent lysosomal or proteasomal degradation (PubMed:21505792). Protects cells against apoptosis and against cytolysis by complement (PubMed:2780565). Intracellular forms interact with ubiquitin and SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes and promote the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:20068069). Promotes proteasomal degradation of COMMD1 and IKBKB (PubMed:20068069). Modulates NF-kappa-B transcriptional activity (PubMed:12882985). A mitochondrial form suppresses BAX-dependent release of cytochrome c into the cytoplasm and inhibit apoptosis (PubMed:16113678, PubMed:17689225). Plays a role in the regulation of cell proliferation (PubMed:19137541). An intracellular form suppresses stress-induced apoptosis by stabilizing mitochondrial membrane integrity through interaction with HSPA5 (PubMed:22689054). Secreted form does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity (PubMed:24073260). Secreted form act as an important modulator during neuronal differentiation through interaction with STMN3 (By similarity). Plays a role in the clearance of immune complexes that arise during cell injury (By similarity).[UniProtKB:P05371][UniProtKB:Q06890][1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] Does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity.[18] Does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity (PubMed:24073260). Promotes cell death through interaction with BCL2L1 that releases and activates BAX (PubMed:21567405).[19] [20]
References
- ↑ Poon S, Easterbrook-Smith SB, Rybchyn MS, Carver JA, Wilson MR. Clusterin is an ATP-independent chaperone with very broad substrate specificity that stabilizes stressed proteins in a folding-competent state. Biochemistry. 2000 Dec 26;39(51):15953-60. PMID:11123922 doi:10.1021/bi002189x
- ↑ Hatters DM, Wilson MR, Easterbrook-Smith SB, Howlett GJ. Suppression of apolipoprotein C-II amyloid formation by the extracellular chaperone, clusterin. Eur J Biochem. 2002 Jun;269(11):2789-94. PMID:12047389 doi:10.1046/j.1432-1033.2002.02957.x
- ↑ Poon S, Rybchyn MS, Easterbrook-Smith SB, Carver JA, Pankhurst GJ, Wilson MR. Mildly acidic pH activates the extracellular molecular chaperone clusterin. J Biol Chem. 2002 Oct 18;277(42):39532-40. PMID:12176985 doi:10.1074/jbc.M204855200
- ↑ Santilli G, Aronow BJ, Sala A. Essential requirement of apolipoprotein J (clusterin) signaling for IkappaB expression and regulation of NF-kappaB activity. J Biol Chem. 2003 Oct 3;278(40):38214-9. PMID:12882985 doi:10.1074/jbc.C300252200
- ↑ Zhang H, Kim JK, Edwards CA, Xu Z, Taichman R, Wang CY. Clusterin inhibits apoptosis by interacting with activated Bax. Nat Cell Biol. 2005 Sep;7(9):909-15. Epub 2005 Aug 21. PMID:16113678 doi:https://dx.doi.org/10.1038/ncb1291
- ↑ Stewart EM, Aquilina JA, Easterbrook-Smith SB, Murphy-Durland D, Jacobsen C, Moestrup S, Wilson MR. Effects of glycosylation on the structure and function of the extracellular chaperone clusterin. Biochemistry. 2007 Feb 6;46(5):1412-22. PMID:17260971 doi:10.1021/bi062082v
- ↑ Kumita JR, Poon S, Caddy GL, Hagan CL, Dumoulin M, Yerbury JJ, Stewart EM, Robinson CV, Wilson MR, Dobson CM. The extracellular chaperone clusterin potently inhibits human lysozyme amyloid formation by interacting with prefibrillar species. J Mol Biol. 2007 May 25;369(1):157-67. PMID:17407782 doi:10.1016/j.jmb.2007.02.095
- ↑ Yerbury JJ, Poon S, Meehan S, Thompson B, Kumita JR, Dobson CM, Wilson MR. The extracellular chaperone clusterin influences amyloid formation and toxicity by interacting with prefibrillar structures. FASEB J. 2007 Aug;21(10):2312-22. PMID:17412999 doi:10.1096/fj.06-7986com
- ↑ Ranney MK, Ahmed IS, Potts KR, Craven RJ. Multiple pathways regulating the anti-apoptotic protein clusterin in breast cancer. Biochim Biophys Acta. 2007 Sep;1772(9):1103-11. PMID:17689225 doi:10.1016/j.bbadis.2007.06.004
- ↑ Rizzi F, Caccamo AE, Belloni L, Bettuzzi S. Clusterin is a short half-life, poly-ubiquitinated protein, which controls the fate of prostate cancer cells. J Cell Physiol. 2009 May;219(2):314-23. PMID:19137541 doi:10.1002/jcp.21671
- ↑ Wyatt AR, Yerbury JJ, Wilson MR. Structural characterization of clusterin-chaperone client protein complexes. J Biol Chem. 2009 Aug 14;284(33):21920-21927. PMID:19535339 doi:10.1074/jbc.M109.033688
- ↑ Wyatt AR, Wilson MR. Identification of human plasma proteins as major clients for the extracellular chaperone clusterin. J Biol Chem. 2010 Feb 5;285(6):3532-3539. PMID:19996109 doi:10.1074/jbc.M109.079566
- ↑ Zoubeidi A, Ettinger S, Beraldi E, Hadaschik B, Zardan A, Klomp LW, Nelson CC, Rennie PS, Gleave ME. Clusterin facilitates COMMD1 and I-kappaB degradation to enhance NF-kappaB activity in prostate cancer cells. Mol Cancer Res. 2010 Jan;8(1):119-30. PMID:20068069 doi:10.1158/1541-7786.MCR-09-0277
- ↑ Wyatt AR, Yerbury JJ, Berghofer P, Greguric I, Katsifis A, Dobson CM, Wilson MR. Clusterin facilitates in vivo clearance of extracellular misfolded proteins. Cell Mol Life Sci. 2011 Dec;68(23):3919-31. PMID:21505792 doi:10.1007/s00018-011-0684-8
- ↑ Li N, Zoubeidi A, Beraldi E, Gleave ME. GRP78 regulates clusterin stability, retrotranslocation and mitochondrial localization under ER stress in prostate cancer. Oncogene. 2013 Apr 11;32(15):1933-42. PMID:22689054 doi:10.1038/onc.2012.212
- ↑ Prochnow H, Gollan R, Rohne P, Hassemer M, Koch-Brandt C, Baiersdörfer M. Non-secreted clusterin isoforms are translated in rare amounts from distinct human mRNA variants and do not affect Bax-mediated apoptosis or the NF-κB signaling pathway. PLoS One. 2013 Sep 20;8(9):e75303. PMID:24073260 doi:10.1371/journal.pone.0075303
- ↑ Jenne DE, Tschopp J. Molecular structure and functional characterization of a human complement cytolysis inhibitor found in blood and seminal plasma: identity to sulfated glycoprotein 2, a constituent of rat testis fluid. Proc Natl Acad Sci U S A. 1989 Sep;86(18):7123-7. PMID:2780565 doi:10.1073/pnas.86.18.7123
- ↑ Prochnow H, Gollan R, Rohne P, Hassemer M, Koch-Brandt C, Baiersdörfer M. Non-secreted clusterin isoforms are translated in rare amounts from distinct human mRNA variants and do not affect Bax-mediated apoptosis or the NF-κB signaling pathway. PLoS One. 2013 Sep 20;8(9):e75303. PMID:24073260 doi:10.1371/journal.pone.0075303
- ↑ Kim N, Yoo JC, Han JY, Hwang EM, Kim YS, Jeong EY, Sun CH, Yi GS, Roh GS, Kim HJ, Kang SS, Cho GJ, Park JY, Choi WS. Human nuclear clusterin mediates apoptosis by interacting with Bcl-XL through C-terminal coiled coil domain. J Cell Physiol. 2012 Mar;227(3):1157-67. PMID:21567405 doi:10.1002/jcp.22836
- ↑ Prochnow H, Gollan R, Rohne P, Hassemer M, Koch-Brandt C, Baiersdörfer M. Non-secreted clusterin isoforms are translated in rare amounts from distinct human mRNA variants and do not affect Bax-mediated apoptosis or the NF-κB signaling pathway. PLoS One. 2013 Sep 20;8(9):e75303. PMID:24073260 doi:10.1371/journal.pone.0075303
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