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Clusterin; Aging-associated gene 4 protein; apolipoprotein J; apo-J; complement cytolysis inhibitor; CLI; complement-associated protein SP-40,40; Ku70-binding protein 1; NA1/NA2; testosterone-repressed prostate message 2; TRPM-2; contains: Clusterin beta chain; apoJalpha; complement cytolysis inhibitor a chain; contains: Clusterin alpha chain; apoJbeta; complement cytolysis inhibitor b chain (CLU, APOJ, CLI, KUB1, AAG4)

Function: - isoform 1 functions as extracellular chaperone that prevents aggregation of non-native proteins - prevents stress-induced aggregation of plasma proteins - inhibits formation of amyloid fibrils by APP, APOC2, B2M, CALCA, CSN3, SNCA & aggregation-prone LYZ variants (in vitro) - circulates with HDL - does not require ATP - maintains partially unfolded proteins in a state appropriate for subsequent refolding by other chaperones, such as HSPA8/HSC70 - does not refold proteins by itself - binding to cell surface receptors triggers internalization of the chaperone-client complex & subsequent lysosomal or proteasomal degradation - secreted isoform 1 protects cells against apoptosis & against cytolysis by complement - intracellular isoforms interact with ubiquitin & SCF E3 ubiquitin-protein ligase complexes & promote the ubiquitination & subsequent proteasomal degradation of target proteins - promotes proteasomal degradation of COMMD1 & IKBKB - modulates NF-kappa-B transcriptional activity - nuclear isoforms promote apoptosis - mitochondrial isoforms suppress BAX-dependent release of cytochrome c into the cytoplasm & inhibit apoptosis. - role in regulation of cell proliferation - isoform 1 is proteolytically cleaved on its way through the secretory system, probably within the Golgi lumen - polyubiquitinated, leading to proteasomal degradation - self-associates & forms higher oligomers - interacts with a broad range of misfolded proteins, including APP, APOC2 & LYZ - slightly acidic pH promotes interaction with misfolded proteins - forms high-molecular weight oligomers upon interaction with misfolded proteins - interacts with APOA1, LRP2, CLUAP1 AND PON1 - interacts with the complement complex - inhibits binding of complement C8 & C9 to the C5b67 complex - interacts (via alpha chain) with XRCC6 - interacts with SYVN1, COMMD1, BTRC, CUL1 & with ubiquitin & SCF E3 ubiquitin-protein ligase complexes - interacts (via alpha chain) with BAX in stressed cells, where BAX undergoes a conformation change leading to association with the mitochondrial membrane - does not interact with BAX in unstressed cells Structure: - heavily N-glycosylated - ~30% of the protein mass is comprised of complex N-linked carbohydrate - antiparallel disulfide-linked heterodimer of an alpha chain & a beta chain - belongs to the clusterin family Compartment: - isoform 1: - secreted - can retrotranslocate from the secretory compartments to the cytosol upon cellular stress - nucleus, cytoplasm, mitochondrial membrane - peripheral membrane, cytoplasmic side - microsome, endoplasmic reticulum - cytoplasmic vesicle, secretory vesicle, chromaffin granule (putative) - isoforms lacking the N-terminal signal sequence are cytoplasmic &/or nuclear - secreted isoforms can retrotranslocate from the secretory compartments to the cytosol upon cellular stress - detected in perinuclear foci that may be aggresomes containing misfolded, ubiquitinated proteins - detected at the mitochondrial membrane upon induction of apoptosis Alternative splicing: named isoforms=5 Expression: - ubiquitous - detected in plasma, cerebrospinal fluid, milk, seminal fluid & colonic mucosa - detected in the germinal center of colon lymphoid nodules & in colon parasympathetic ganglia of the Auerbach plexus (at protein level) - detected in brain, testis, ovary, liver & pancreas, & at lower levels in kidney, heart, spleen & lung - up-regulated in response to enterovirus 71 (EV71) infection (at protein level) - up-regulated by agents that induce apoptosis, both at mRNA & protein level - isoform 1 is up-regulated by androgen - isoform 2 is down-regulated by androgen Pathology: - clusterin is absent in erythrocytes of patients with paroxysmal nocturnal hemoglobinuria (PNH) - clusterin may play neuroprotective role in dementia [5] - a minor isoform that has been detected in a breast cancer cell line, but not in any other tissues or cell lines Comparative biology: - plasma collected from voluntarily running mice infused into sedentary mice reduces baseline neuroinflammatory gene expression & experimentally-induced neuroinflammation [8] - increase in complement cascade inhibitors including clusterin* * persons with mild cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of clusterin [8]

Interactions

molecular events

Related

Clusterin Ag in tissue clusterin-associated protein 1 (CLUAP1, KIAA0643) Clusterin-like protein 1 precursor (retinal-specific clusterin-like protein, CLUL1)

General

chromogranin; secretogranin;granin glycoprotein multisubunit protein phosphoprotein protease inhibitor

Properties

SIZE: entity length = 449 aa MW = 52 kD COMPARTMENT: mitochondria cytoplasm cell nucleus endoplasmic reticulum MOTIF: signal sequence {1-22} nuclear translocation signal {78-81} N-glycosylation site {N86} cysteine residue {C102} MODIFICATION: cysteine residue {C-INTERCHAIN} N-glycosylation site {N103} cysteine residue {C113} MODIFICATION: cysteine residue {C-INTERCHAIN} cysteine residue {C116} MODIFICATION: cysteine residue {C-INTERCHAIN} cysteine residue {C121} MODIFICATION: cysteine residue {C-INTERCHAIN} cysteine residue {C129} MODIFICATION: cysteine residue {C-INTERCHAIN} N-glycosylation site {N145} N-glycosylation site {N291} N-glycosylation site {N317} N-glycosylation site {N354} N-glycosylation site {N374} Thr phosphorylation site {T393} Ser phosphorylation site {S394} Ser phosphorylation site {S396} nuclear translocation signal {443-447} INHIBITS: protease MISC-INFO: ISOELECTIC_POINT 5.6

Database Correlations

OMIM 185430 UniProt P10909 Pfam PF01093 Entrez Gene 1191 Kegg hsa:1191

References

  1. Jenne DE, Tschopp J. Clusterin: the intriguing guises of a widely expressed glycoprotein. Trends Biochem Sci. 1992 Apr;17(4):154-9. Review. PMID: 1585460
  2. Johnson & Finch Neurosci Abs 1990 #83.8
  3. Huttner WB, Gerdes HH, Rosa P. The granin (chromogranin/secretogranin) family. Trends Biochem Sci. 1991 Jan;16(1):27-30. Review. PMID: 2053134
  4. Entrez Gene :accession 1191
  5. Schrijvers EMC et al. Plasma clusterin and the risk of Alzheimer disease. JAMA 2011 Apr 6; 305:1322. PMID: 21467285
  6. UniProt :accession P10909
  7. NIEHS-SNPs http://egp.gs.washington.edu/data/clu/
  8. De Miguel Z, Khoury N, Betley MJ et al. Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature 2021 Dec; 600:494. PMID: 34880498 https://www.nature.com/articles/s41586-021-04183-x

Component-of

complement complex