P25473 · CLUS_CANLF
- ProteinClusterin
- GeneCLU
- StatusUniProtKB reviewed (Swiss-Prot)
- Amino acids445 (go to sequence)
- Protein existenceEvidence at transcript level
- Annotation score5/5
Function
function
Functions as extracellular chaperone that prevents aggregation of non native proteins. Prevents stress-induced aggregation of blood plasma proteins. Inhibits formation of amyloid fibrils by APP, APOC2, B2M, CALCA, CSN3, SNCA and aggregation-prone LYZ variants (in vitro). 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 (By similarity).
Binding to cell surface receptors triggers internalization of the chaperone-client complex and subsequent lysosomal or proteasomal degradation (PubMed:11697889).
When secreted, protects cells against apoptosis and against cytolysis by complement. 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. Promotes proteasomal degradation of COMMD1 and IKBKB. Modulates NF-kappa-B transcriptional activity (By similarity).
Following stress, promotes apoptosis (By similarity).
Inhibits apoptosis when associated with the mitochondrial membrane by interference with BAX-dependent release of cytochrome c into the cytoplasm. Plays a role in the regulation of cell proliferation. An intracellular form suppresses stress-induced apoptosis by stabilizing mitochondrial membrane integrity through interaction with HSPA5. Secreted form does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity (By similarity).
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).
Binding to cell surface receptors triggers internalization of the chaperone-client complex and subsequent lysosomal or proteasomal degradation (PubMed:11697889).
When secreted, protects cells against apoptosis and against cytolysis by complement. 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. Promotes proteasomal degradation of COMMD1 and IKBKB. Modulates NF-kappa-B transcriptional activity (By similarity).
Following stress, promotes apoptosis (By similarity).
Inhibits apoptosis when associated with the mitochondrial membrane by interference with BAX-dependent release of cytochrome c into the cytoplasm. Plays a role in the regulation of cell proliferation. An intracellular form suppresses stress-induced apoptosis by stabilizing mitochondrial membrane integrity through interaction with HSPA5. Secreted form does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity (By similarity).
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).
GO annotations
Keywords
- Molecular function
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameClusterin
- Alternative names
- Cleaved into 2 chains
Gene names
Organism names
- Strain
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Laurasiatheria > Carnivora > Caniformia > Canidae > Canis
Accessions
- Primary accessionP25473
Proteomes
Subcellular Location
UniProt Annotation
GO Annotation
Mitochondrion membrane ; Peripheral membrane protein
Note: 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 mitochondrion membrane upon induction of apoptosis. Under ER stress, a immaturely glycosylated pre-secreted form retrotranslocates from the endoplasmic reticulum (ER)-Golgi network to the cytoplasm to localize in the mitochondria through HSPA5 interaction. ER stress reduces secretion. Under the stress, minor amounts of non-secreted forms accumulate in cytoplasm.
Keywords
- Cellular component
PTM/Processing
Features
Showing features for signal, chain, glycosylation, disulfide bond, modified residue.
Type | ID | Position(s) | Description | ||
---|---|---|---|---|---|
Signal | 1-22 | ||||
Chain | PRO_0000005524 | 23-226 | Clusterin beta chain | ||
Chain | PRO_0000005523 | 23-445 | Clusterin | ||
Glycosylation | 86 | N-linked (GlcNAc...) asparagine | |||
Disulfide bond | 102↔309 | Interchain (between beta and alpha chains) | |||
Glycosylation | 103 | N-linked (GlcNAc...) asparagine | |||
Disulfide bond | 113↔301 | Interchain (between beta and alpha chains) | |||
Disulfide bond | 116↔298 | Interchain (between beta and alpha chains) | |||
Disulfide bond | 121↔291 | Interchain (between beta and alpha chains) | |||
Disulfide bond | 129↔281 | Interchain (between beta and alpha chains) | |||
Modified residue | 133 | Phosphoserine | |||
Glycosylation | 145 | N-linked (GlcNAc...) asparagine | |||
Chain | PRO_0000005525 | 227-445 | Clusterin alpha chain | ||
Glycosylation | 277 | N-linked (GlcNAc...) asparagine | |||
Glycosylation | 287 | N-linked (GlcNAc...) asparagine | |||
Glycosylation | 350 | N-linked (GlcNAc...) asparagine | |||
Glycosylation | 370 | N-linked (GlcNAc...) asparagine | |||
Modified residue | 392 | Phosphoserine | |||
Post-translational modification
Proteolytically cleaved on its way through the secretory system, probably within the Golgi lumen (By similarity) (PubMed:7744793).
Proteolytic cleavage is not necessary for its chaperone activity. All non-secreted forms are not proteolytically cleaved. Chaperone activity of uncleaved forms is dependent on a non-reducing environment (By similarity).
This proteolytic maturation is disulfide bond formation dependent (PubMed:7744793).
Proteolytic cleavage is not necessary for its chaperone activity. All non-secreted forms are not proteolytically cleaved. Chaperone activity of uncleaved forms is dependent on a non-reducing environment (By similarity).
This proteolytic maturation is disulfide bond formation dependent (PubMed:7744793).
Polyubiquitinated, leading to proteasomal degradation. Under cellular stress, the intracellular level of cleaved form is reduced due to proteasomal degradation.
Heavily N-glycosylated. About 30% of the protein mass is comprised of complex N-linked carbohydrate. Endoplasmic reticulum (ER) stress induces changes in glycosylation status and increases level of hypoglycosylated forms. Core carbohydrates are essential for chaperone activity. Non-secreted forms are hypoglycosylated or unglycosylated.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Gene expression databases
Interaction
Subunit
Antiparallel disulfide-linked heterodimer of an alpha chain and a beta chain. Self-associates and forms higher oligomers. Interacts with a broad range of misfolded proteins, including APP, APOC2 and 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. Interacts (via alpha chain) with XRCC6. Interacts with SYVN1, COMMD1, BTRC, CUL1 and with ubiquitin and SCF (SKP1-CUL1-F-box protein) 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. Found in a complex with LTF, CLU, EPPIN and SEMG1. Interacts (immaturely glycosylated pre-secreted form) with HSPA5; this interaction promotes CLU stability and facilitates stress-induced CLU retrotranslocation from the secretory pathway to the mitochondria, thereby reducing stress-induced apoptosis by stabilizing mitochondrial membrane integrity. Interacts with BCL2L1; this interaction releases and activates BAX and promotes cell death. Interacts with TGFBR2 and ACVR1 (By similarity).
Interacts (secreted form) with STMN3; this interaction may act as an important modulator during neuronal differentiation (By similarity).
Interacts with VLDLR and LRP8 (By similarity).
Interacts (secreted form) with STMN3; this interaction may act as an important modulator during neuronal differentiation (By similarity).
Interacts with VLDLR and LRP8 (By similarity).
Protein-protein interaction databases
Structure
Family & Domains
Features
Showing features for motif.
Type | ID | Position(s) | Description | ||
---|---|---|---|---|---|
Motif | 78-81 | Nuclear localization signal | |||
Motif | 439-443 | Nuclear localization signal | |||
Sequence similarities
Belongs to the clusterin family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
- Length445
- Mass (Da)51,790
- Last updated1992-05-01 v1
- MD5 Checksum63A6D0BC4A4CE6C6CDDCC26C0FF732CD
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
M55251 EMBL· GenBank· DDBJ | AAA30846.1 EMBL· GenBank· DDBJ | mRNA |