P10909 · CLUS_HUMAN
- ProteinClusterin
- GeneCLU
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids449 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Isoform 1
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).
Isoform 6
Isoform 4
Promotes cell death through interaction with BCL2L1 that releases and activates BAX (PubMed:21567405).
Features
Showing features for site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 227-228 | Cleavage | ||||
Sequence: RS |
GO annotations
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameClusterin
- Alternative names
- Cleaved into 2 chains
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP10909
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Detected in perinuclear foci that may be aggresomes containing misfolded, ubiquitinated proteins (PubMed:20068069).
Detected at the mitochondrion membrane upon induction of apoptosis (PubMed:17689225).
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 (PubMed:22689054).
ER stress reduces secretion (PubMed:22689054).
Under the stress, minor amounts of non-secreted forms accumulate in cytoplasm (PubMed:17451556, PubMed:22689054, PubMed:24073260).
Non-secreted forms emerge mainly from failed translocation, alternative splicing or non-canonical initiation start codon (PubMed:12551933, PubMed:24073260).
Isoform 1
Isoform 4
Isoform 6
Keywords
- Cellular component
Disease & Variants
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 86 | Decreases molecular mass of beta chain; when associated with Q-103 and Q-145. | ||||
Sequence: N → Q | ||||||
Mutagenesis | 103 | Decreases molecular mass of beta chain; when associated with Q-86 and Q-145. | ||||
Sequence: N → Q | ||||||
Mutagenesis | 145 | Decreases molecular mass of beta chain; when associated with Q-86 and Q-103. | ||||
Sequence: N → Q | ||||||
Mutagenesis | 226 | Does not affect proteolytic cleavage. | ||||
Sequence: V → T | ||||||
Mutagenesis | 227 | Affects proteolytic cleavage. | ||||
Sequence: R → Q | ||||||
Mutagenesis | 291 | Decreases molecular mass of alpha chain; when associated with Q-354 and Q-374. Decreases secretion; when associated with Q-354 and Q-374. | ||||
Sequence: N → Q | ||||||
Natural variant | VAR_019366 | 317 | in dbSNP:rs9331936 | |||
Sequence: N → H | ||||||
Natural variant | VAR_019367 | 328 | in dbSNP:rs9331938 | |||
Sequence: D → N | ||||||
Mutagenesis | 354 | Decreases molecular mass of alpha chain; when associated with Q-291 and Q-374. Decreases secretion; when associated with Q-291 and Q-374. | ||||
Sequence: N → Q | ||||||
Mutagenesis | 374 | Decreases molecular mass of alpha chain; when associated with Q-291 and Q-354. Decreases secretion; when associated with Q-291 and Q-354. | ||||
Sequence: N → Q | ||||||
Natural variant | VAR_019368 | 396 | in dbSNP:rs13494 | |||
Sequence: S → L |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 545 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for signal, chain, glycosylation, disulfide bond, modified residue, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Signal | 1-22 | UniProt | |||||
Sequence: MMKTLLLFVGLLLTWESGQVLG | |||||||
Chain | PRO_0000005530 | 23-227 | UniProt | Clusterin beta chain | |||
Sequence: DQTVSDNELQEMSNQGSKYVNKEIQNAVNGVKQIKTLIEKTNEERKTLLSNLEEAKKKKEDALNETRESETKLKELPGVCNETMMALWEECKPCLKQTCMKFYARVCRSGSGLVGRQLEEFLNQSSPFYFWMNGDRIDSLLENDRQQTHMLDVMQDHFSRASSIIDELFQDRFFTREPQDTYHYLPFSLPHRRPHFFFPKSRIVR | |||||||
Chain | PRO_0000005529 | 23-449 | UniProt | Clusterin | |||
Sequence: DQTVSDNELQEMSNQGSKYVNKEIQNAVNGVKQIKTLIEKTNEERKTLLSNLEEAKKKKEDALNETRESETKLKELPGVCNETMMALWEECKPCLKQTCMKFYARVCRSGSGLVGRQLEEFLNQSSPFYFWMNGDRIDSLLENDRQQTHMLDVMQDHFSRASSIIDELFQDRFFTREPQDTYHYLPFSLPHRRPHFFFPKSRIVRSLMPFSPYEPLNFHAMFQPFLEMIHEAQQAMDIHFHSPAFQHPPTEFIREGDDDRTVCREIRHNSTGCLRMKDQCDKCREILSVDCSTNNPSQAKLRRELDESLQVAERLTRKYNELLKSYQWKMLNTSSLLEQLNEQFNWVSRLANLTQGEDQYYLRVTTVASHTSDSDVPSGVTEVVVKLFDSDPITVTVPVEVSRKNPKFMETVAEKALQEYRKKHREE | |||||||
Glycosylation | 86 | UniProt | N-linked (GlcNAc...) (complex) asparagine | ||||
Sequence: N | |||||||
Disulfide bond | 102↔313 | UniProt | Interchain (between beta and alpha chains) | ||||
Sequence: CNETMMALWEECKPCLKQTCMKFYARVCRSGSGLVGRQLEEFLNQSSPFYFWMNGDRIDSLLENDRQQTHMLDVMQDHFSRASSIIDELFQDRFFTREPQDTYHYLPFSLPHRRPHFFFPKSRIVRSLMPFSPYEPLNFHAMFQPFLEMIHEAQQAMDIHFHSPAFQHPPTEFIREGDDDRTVCREIRHNSTGCLRMKDQCDKCREILSVDC | |||||||
Glycosylation | 103 | UniProt | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | |||||||
Disulfide bond | 113↔305 | UniProt | Interchain (between beta and alpha chains) | ||||
Sequence: CKPCLKQTCMKFYARVCRSGSGLVGRQLEEFLNQSSPFYFWMNGDRIDSLLENDRQQTHMLDVMQDHFSRASSIIDELFQDRFFTREPQDTYHYLPFSLPHRRPHFFFPKSRIVRSLMPFSPYEPLNFHAMFQPFLEMIHEAQQAMDIHFHSPAFQHPPTEFIREGDDDRTVCREIRHNSTGCLRMKDQCDKC | |||||||
Disulfide bond | 116↔302 | UniProt | Interchain (between beta and alpha chains) | ||||
Sequence: CLKQTCMKFYARVCRSGSGLVGRQLEEFLNQSSPFYFWMNGDRIDSLLENDRQQTHMLDVMQDHFSRASSIIDELFQDRFFTREPQDTYHYLPFSLPHRRPHFFFPKSRIVRSLMPFSPYEPLNFHAMFQPFLEMIHEAQQAMDIHFHSPAFQHPPTEFIREGDDDRTVCREIRHNSTGCLRMKDQC | |||||||
Disulfide bond | 121↔295 | UniProt | Interchain (between beta and alpha chains) | ||||
Sequence: CMKFYARVCRSGSGLVGRQLEEFLNQSSPFYFWMNGDRIDSLLENDRQQTHMLDVMQDHFSRASSIIDELFQDRFFTREPQDTYHYLPFSLPHRRPHFFFPKSRIVRSLMPFSPYEPLNFHAMFQPFLEMIHEAQQAMDIHFHSPAFQHPPTEFIREGDDDRTVCREIRHNSTGC | |||||||
Disulfide bond | 129↔285 | UniProt | Interchain (between beta and alpha chains) | ||||
Sequence: CRSGSGLVGRQLEEFLNQSSPFYFWMNGDRIDSLLENDRQQTHMLDVMQDHFSRASSIIDELFQDRFFTREPQDTYHYLPFSLPHRRPHFFFPKSRIVRSLMPFSPYEPLNFHAMFQPFLEMIHEAQQAMDIHFHSPAFQHPPTEFIREGDDDRTVC | |||||||
Modified residue | 133 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Glycosylation | 145 | UniProt | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | |||||||
Chain | PRO_0000005531 | 228-449 | UniProt | Clusterin alpha chain | |||
Sequence: SLMPFSPYEPLNFHAMFQPFLEMIHEAQQAMDIHFHSPAFQHPPTEFIREGDDDRTVCREIRHNSTGCLRMKDQCDKCREILSVDCSTNNPSQAKLRRELDESLQVAERLTRKYNELLKSYQWKMLNTSSLLEQLNEQFNWVSRLANLTQGEDQYYLRVTTVASHTSDSDVPSGVTEVVVKLFDSDPITVTVPVEVSRKNPKFMETVAEKALQEYRKKHREE | |||||||
Glycosylation | 291 | UniProt | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | |||||||
Glycosylation | 354 | UniProt | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | |||||||
Glycosylation | 374 | UniProt | N-linked (GlcNAc...) (complex) asparagine | ||||
Sequence: N | |||||||
Modified residue | 396 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 396 | PRIDE | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Proteolytic cleavage is not necessary for its chaperone activity (PubMed:25402950).
All non-secreted forms are not proteolytically cleaved (PubMed:24073260).
Chaperone activity of uncleaved forms is dependent on a non-reducing environment (PubMed:25402950).
Under cellular stress, the intracellular level of cleaved form is reduced due to proteasomal degradation (PubMed:17451556).
About 30% of the protein mass is comprised of complex N-linked carbohydrate (PubMed:2387851).
Endoplasmic reticulum (ER) stress induces changes in glycosylation status and increases level of hypoglycosylated forms (PubMed:22689054).
Core carbohydrates are essential for chaperone activity (PubMed:25402950).
Non-secreted forms are hypoglycosylated or unglycosylated (PubMed:24073260).
Keywords
- PTM
Proteomic databases
2D gel databases
PTM databases
Expression
Tissue specificity
Induction
Up-regulated by agents that induce apoptosis, both at mRNA and protein level (PubMed:17689225).
Isoform 1 is up-regulated by androgen (PubMed:17148459).
Isoform 2 is down-regulated by androgen (PubMed:17148459).
Gene expression databases
Organism-specific databases
Interaction
Subunit
Self-associates and forms higher oligomers (PubMed:1903064).
Interacts with a broad range of misfolded proteins, including APP, APOC2 and LYZ (PubMed:17407782, PubMed:17412999, PubMed:8328966).
Slightly acidic pH promotes interaction with misfolded proteins (PubMed:12176985).
Forms high-molecular weight oligomers upon interaction with misfolded proteins (PubMed:19535339).
Interacts with APOA1, LRP2, CLUAP1 and PON1 (PubMed:15480429, PubMed:17260971, PubMed:1742316, PubMed:1903064, PubMed:8292612).
Interacts with the complement complex (PubMed:2601725).
Interacts (via alpha chain) with XRCC6 (By similarity).
Interacts with SYVN1, COMMD1, BTRC, CUL1 and with ubiquitin and SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes (PubMed:17451556, PubMed:20068069).
Interacts (via alpha chain) with BAX in stressed cells, where BAX undergoes a conformation change leading to association with the mitochondrial membrane (PubMed:16113678).
Does not interact with BAX in unstressed cells (PubMed:16113678).
Found in a complex with LTF, CLU, EPPIN and SEMG1 (PubMed:17567961).
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 (PubMed:22689054).
Interacts (isoform 4) with BCL2L1; this interaction releases and activates BAX and promotes cell death (PubMed:21567405).
Interacts with TGFBR2 and ACVR1 (PubMed:8555189).
Interacts (secreted form) with STMN3; this interaction may act as an important modulator during neuronal differentiation (By similarity).
Interacts with VLDLR and LRP8 (PubMed:24381170).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | P10909 | ADCYAP1 P18509 | 4 | EBI-1104674, EBI-8588930 | |
BINARY | P10909 | APP P05067 | 3 | EBI-1104674, EBI-77613 | |
BINARY | P10909 | APP PRO_0000000093 P05067 | 4 | EBI-1104674, EBI-2431589 | |
BINARY | P10909 | DISC1 Q9NRI5 | 4 | EBI-1104674, EBI-529989 | |
BINARY | P10909 | FOS P01100 | 2 | EBI-1104674, EBI-852851 | |
BINARY | P10909 | PDIA3 P30101 | 2 | EBI-1104674, EBI-979862 | |
BINARY | P10909 | PPARG P37231 | 3 | EBI-1104674, EBI-781384 | |
BINARY | P10909 | SNCA P37840 | 4 | EBI-1104674, EBI-985879 | |
BINARY | P10909-4 | BCL2L1 Q07817-1 | 6 | EBI-4322678, EBI-287195 | |
BINARY | P10909-5 | APP PRO_0000000092 P05067 | 2 | EBI-10961636, EBI-821758 | |
BINARY | P10909-5 | MSRB1 Q9NZV6 | 10 | EBI-10961636, EBI-12330065 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for motif.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Motif | 78-81 | Nuclear localization signal | ||||
Sequence: KKKK | ||||||
Motif | 443-447 | Nuclear localization signal | ||||
Sequence: RKKHR |
Sequence similarities
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence & Isoforms
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
This entry describes 6 isoforms produced by Alternative splicing.
P10909-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- Synonyms2, CLU35, sCLU
- NoteMajor isoform. Major isoform. Detectable at protein level in stressed and unstressed cells (PubMed:24073260).
- Length449
- Mass (Da)52,495
- Last updated1989-07-01 v1
- Checksum9583DE4CCECC169F
P10909-2
- Name2
- Synonyms1, CLU34
- Differences from canonical
- 1-1: M → MQVCSQPQRGCVREQSAINTAPPSAHNAASPGGARGHRVPLTEACKDSRIGGM
P10909-3
- Name3
- Differences from canonical
- 1-175: Missing
P10909-4
- Name4
- SynonymsnCLU
- Differences from canonical
- 1-33: Missing
P10909-5
- Name5
- SynonymsCLU36
- Differences from canonical
- 1-1: M → MEACKDSRIGGM
P10909-6
- Name6
Computationally mapped potential isoform sequences
There are 10 potential isoforms mapped to this entry
Sequence caution
Features
Showing features for alternative sequence, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_037661 | 1 | in isoform 2 | |||
Sequence: M → MQVCSQPQRGCVREQSAINTAPPSAHNAASPGGARGHRVPLTEACKDSRIGGM | ||||||
Alternative sequence | VSP_041477 | 1 | in isoform 5 | |||
Sequence: M → MEACKDSRIGGM | ||||||
Alternative sequence | VSP_060188 | 1-20 | in isoform 6 | |||
Sequence: Missing | ||||||
Alternative sequence | VSP_041476 | 1-33 | in isoform 4 | |||
Sequence: Missing | ||||||
Alternative sequence | VSP_041475 | 1-175 | in isoform 3 | |||
Sequence: Missing | ||||||
Alternative sequence | VSP_060192 | 21 | in isoform 6 | |||
Sequence: L → M | ||||||
Sequence conflict | 28 | in Ref. 10; AA sequence and 14; AA sequence | ||||
Sequence: D → S | ||||||
Sequence conflict | 47 | in Ref. 11; AA sequence | ||||
Sequence: Q → H | ||||||
Sequence conflict | 52 | in Ref. 11; AA sequence | ||||
Sequence: G → Q | ||||||
Sequence conflict | 172 | in Ref. 6; CAI45990 | ||||
Sequence: M → V | ||||||
Sequence conflict | 224 | in Ref. 4; BAG36598 | ||||
Sequence: R → L | ||||||
Sequence conflict | 305 | in Ref. 10; AA sequence | ||||
Sequence: C → M | ||||||
Sequence conflict | 388 | in Ref. 6; CAI45990 | ||||
Sequence: T → M | ||||||
Sequence conflict | 411 | in Ref. 4; BAG36598 | ||||
Sequence: D → G |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
M25915 EMBL· GenBank· DDBJ | AAA35692.1 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
M63379 EMBL· GenBank· DDBJ | AAB06507.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
M63376 EMBL· GenBank· DDBJ | AAB06507.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
M63377 EMBL· GenBank· DDBJ | AAB06507.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
M63378 EMBL· GenBank· DDBJ | AAB06507.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
M64722 EMBL· GenBank· DDBJ | AAB06508.1 EMBL· GenBank· DDBJ | mRNA | Sequence problems. | |
AK093399 EMBL· GenBank· DDBJ | BAG52708.1 EMBL· GenBank· DDBJ | mRNA | ||
AK313870 EMBL· GenBank· DDBJ | BAG36598.1 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
CR599675 EMBL· GenBank· DDBJ | - | mRNA | No translation available. | |
BX648414 EMBL· GenBank· DDBJ | CAI45990.1 EMBL· GenBank· DDBJ | mRNA | ||
AY341244 EMBL· GenBank· DDBJ | AAP88927.1 EMBL· GenBank· DDBJ | Genomic DNA | Different initiation | |
AF311103 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
BC010514 EMBL· GenBank· DDBJ | AAH10514.1 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
BC019588 EMBL· GenBank· DDBJ | AAH19588.1 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
BU150467 EMBL· GenBank· DDBJ | - | mRNA | No translation available. | |
J02908 EMBL· GenBank· DDBJ | AAA51765.1 EMBL· GenBank· DDBJ | mRNA | ||
M74816 EMBL· GenBank· DDBJ | AAA60321.1 EMBL· GenBank· DDBJ | mRNA | ||
L00974 EMBL· GenBank· DDBJ | AAA60567.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
X14723 EMBL· GenBank· DDBJ | CAA32847.1 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
AY513288 EMBL· GenBank· DDBJ | AAT08041.1 EMBL· GenBank· DDBJ | mRNA | Different initiation |