CLUS_RABIT
ID CLUS_RABIT Reviewed; 447 AA.
AC Q9XSC5;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 25-MAY-2022, entry version 105.
DE RecName: Full=Clusterin {ECO:0000303|PubMed:11560857};
DE AltName: Full=Apolipoprotein J {ECO:0000303|PubMed:11560857};
DE Short=Apo-J;
DE Contains:
DE RecName: Full=Clusterin beta chain;
DE Contains:
DE RecName: Full=Clusterin alpha chain;
DE Flags: Precursor;
GN Name=CLU; Synonyms=ApoJ {ECO:0000303|PubMed:11560857};
OS Oryctolagus cuniculus (Rabbit).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX NCBI_TaxID=9986;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Japanese white;
RX PubMed=11560857; DOI=10.1161/hc3701.095583;
RA Miyata M., Biro S., Kaieda H., Eto H., Orihara K., Kihara T., Obata H.,
RA Matsushita N., Matsuyama T., Tei C.;
RT "Apolipoprotein J/clusterin is induced in vascular smooth muscle cells
RT after vascular injury.";
RL Circulation 104:1407-1412(2001).
CC -!- FUNCTION: Functions as extracellular chaperone that prevents
CC aggregation of non native proteins. Prevents stress-induced aggregation
CC of blood plasma proteins. Inhibits formation of amyloid fibrils by APP,
CC APOC2, B2M, CALCA, CSN3, SNCA and aggregation-prone LYZ variants (in
CC vitro). Does not require ATP. Maintains partially unfolded proteins in
CC a state appropriate for subsequent refolding by other chaperones, such
CC as HSPA8/HSC70. Does not refold proteins by itself. Binding to cell
CC surface receptors triggers internalization of the chaperone-client
CC complex and subsequent lysosomal or proteasomal degradation. When
CC secreted, protects cells against apoptosis and against cytolysis by
CC complement. Intracellular forms interact with ubiquitin and SCF (SKP1-
CC CUL1-F-box protein) E3 ubiquitin-protein ligase complexes and promote
CC the ubiquitination and subsequent proteasomal degradation of target
CC proteins. Promotes proteasomal degradation of COMMD1 and IKBKB.
CC Modulates NF-kappa-B transcriptional activity (By similarity).
CC Following stress, promotes apoptosis (By similarity). Inhibits
CC apoptosis when associated with the mitochondrial membrane by
CC interference with BAX-dependent release of cytochrome c into the
CC cytoplasm. Plays a role in the regulation of cell proliferation. An
CC intracellular form suppresses stress-induced apoptosis by stabilizing
CC mitochondrial membrane integrity through interaction with HSPA5.
CC Secreted form does not affect caspase or BAX-mediated intrinsic
CC apoptosis and TNF-induced NF-kappa-B-activity (By similarity). Secreted
CC form act as an important modulator during neuronal differentiation
CC through interaction with STMN3 (By similarity). Plays a role in the
CC clearance of immune complexes that arise during cell injury (By
CC similarity). {ECO:0000250|UniProtKB:P05371,
CC ECO:0000250|UniProtKB:P10909, ECO:0000250|UniProtKB:Q06890}.
CC -!- SUBUNIT: Antiparallel disulfide-linked heterodimer of an alpha chain
CC and a beta chain. Self-associates and forms higher oligomers. Interacts
CC with a broad range of misfolded proteins, including APP, APOC2 and LYZ.
CC Slightly acidic pH promotes interaction with misfolded proteins. Forms
CC high-molecular weight oligomers upon interaction with misfolded
CC proteins. Interacts with APOA1, LRP2, CLUAP1 and PON1. Interacts with
CC the complement complex. Interacts (via alpha chain) with XRCC6.
CC Interacts with SYVN1, COMMD1, BTRC, CUL1 and with ubiquitin and SCF
CC (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes.
CC Interacts (via alpha chain) with BAX in stressed cells, where BAX
CC undergoes a conformation change leading to association with the
CC mitochondrial membrane. Does not interact with BAX in unstressed cells.
CC Found in a complex with LTF, CLU, EPPIN and SEMG1. Interacts
CC (immaturely glycosylated pre-secreted form) with HSPA5; this
CC interaction promotes CLU stability and facilitates stress-induced CLU
CC retrotranslocation from the secretory pathway to the mitochondria,
CC thereby reducing stress-induced apoptosis by stabilizing mitochondrial
CC membrane integrity. Interacts with BCL2L1; this interaction releases
CC and activates BAX and promotes cell death. Interacts with TGFBR2 and
CC ACVR1 (By similarity). Interacts (secreted form) with STMN3; this
CC interaction may act as an important modulator during neuronal
CC differentiation (By similarity). Interacts with VLDLR and LRP8 (By
CC similarity). {ECO:0000250|UniProtKB:P05371,
CC ECO:0000250|UniProtKB:P10909}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P10909}. Nucleus
CC {ECO:0000250|UniProtKB:P10909}. Cytoplasm
CC {ECO:0000250|UniProtKB:P10909}. Mitochondrion membrane
CC {ECO:0000250|UniProtKB:P10909}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:P10909}; Cytoplasmic side
CC {ECO:0000250|UniProtKB:P10909}. Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:P10909}. Microsome
CC {ECO:0000250|UniProtKB:P10909}. Endoplasmic reticulum
CC {ECO:0000250|UniProtKB:P10909}. Mitochondrion
CC {ECO:0000250|UniProtKB:P10909}. Mitochondrion membrane
CC {ECO:0000250|UniProtKB:P10909}. Cytoplasm, perinuclear region
CC {ECO:0000250|UniProtKB:P05371}. Cytoplasmic vesicle, secretory vesicle,
CC chromaffin granule. Note=Can retrotranslocate from the secretory
CC compartments to the cytosol upon cellular stress. Detected in
CC perinuclear foci that may be aggresomes containing misfolded,
CC ubiquitinated proteins. Detected at the mitochondrion membrane upon
CC induction of apoptosis. Under ER stress, a immaturely glycosylated pre-
CC secreted form retrotranslocates from the endoplasmic reticulum (ER)-
CC Golgi network to the cytoplasm to localize in the mitochondria through
CC HSPA5 interaction. ER stress reduces secretion. Under the stress, minor
CC amounts of non-secreted forms accumulate in cytoplasm.
CC {ECO:0000250|UniProtKB:P10909}.
CC -!- PTM: Proteolytically cleaved on its way through the secretory system,
CC probably within the Golgi lumen. Proteolytic cleavage is not necessary
CC for its chaperone activity. All non-secreted forms are not
CC proteolytically cleaved. Chaperone activity of uncleaved forms is
CC dependent on a non-reducing envoronment.
CC {ECO:0000250|UniProtKB:P10909}.
CC -!- PTM: Polyubiquitinated, leading to proteasomal degradation. Under
CC cellular stress, the intracellular level of cleaved form is reduced due
CC to proteasomal degradation. {ECO:0000250|UniProtKB:P10909}.
CC -!- PTM: Heavily N-glycosylated. About 30% of the protein mass is comprised
CC of complex N-linked carbohydrate. Endoplasmic reticulum (ER) stress
CC induces changes in glycosylation status and increases level of
CC hypoglycosylated forms. Core carbohydrates are essential for chaperone
CC activity. Non-secreted forms are hypoglycosylated or unglycosylated.
CC {ECO:0000250|UniProtKB:P10909}.
CC -!- SIMILARITY: Belongs to the clusterin family. {ECO:0000305}.
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DR EMBL; AF118852; AAD24461.1; -; mRNA.
DR RefSeq; NP_001075518.1; NM_001082049.2.
DR AlphaFoldDB; Q9XSC5; -.
DR SMR; Q9XSC5; -.
DR STRING; 9986.ENSOCUP00000005178; -.
DR PRIDE; Q9XSC5; -.
DR GeneID; 100008713; -.
DR KEGG; ocu:100008713; -.
DR CTD; 1191; -.
DR eggNOG; ENOG502RBQP; Eukaryota.
DR InParanoid; Q9XSC5; -.
DR OrthoDB; 973835at2759; -.
DR Proteomes; UP000001811; Unplaced.
DR GO; GO:0042583; C:chromaffin granule; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; ISS:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISS:UniProtKB.
DR GO; GO:0005743; C:mitochondrial inner membrane; ISS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0099020; C:perinuclear endoplasmic reticulum lumen; ISS:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISS:UniProtKB.
DR GO; GO:0034366; C:spherical high-density lipoprotein particle; ISS:UniProtKB.
DR GO; GO:0051787; F:misfolded protein binding; ISS:UniProtKB.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISS:UniProtKB.
DR GO; GO:0051082; F:unfolded protein binding; ISS:UniProtKB.
DR GO; GO:0061077; P:chaperone-mediated protein folding; ISS:UniProtKB.
DR GO; GO:0002434; P:immune complex clearance; ISS:UniProtKB.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; ISS:UniProtKB.
DR GO; GO:1905907; P:negative regulation of amyloid fibril formation; ISS:UniProtKB.
DR GO; GO:1902230; P:negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage; ISS:UniProtKB.
DR GO; GO:0031333; P:negative regulation of protein-containing complex assembly; ISS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; ISS:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR GO; GO:0048260; P:positive regulation of receptor-mediated endocytosis; ISS:UniProtKB.
DR GO; GO:2000060; P:positive regulation of ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; ISS:UniProtKB.
DR GO; GO:0042127; P:regulation of cell population proliferation; ISS:UniProtKB.
DR GO; GO:0051788; P:response to misfolded protein; ISS:UniProtKB.
DR InterPro; IPR016016; Clusterin.
DR InterPro; IPR000753; Clusterin-like.
DR InterPro; IPR016015; Clusterin_C.
DR InterPro; IPR033986; Clusterin_CS.
DR InterPro; IPR016014; Clusterin_N.
DR PANTHER; PTHR10970; PTHR10970; 1.
DR PANTHER; PTHR10970:SF1; PTHR10970:SF1; 1.
DR Pfam; PF01093; Clusterin; 1.
DR PIRSF; PIRSF002368; Clusterin; 1.
DR SMART; SM00035; CLa; 1.
DR SMART; SM00030; CLb; 1.
DR PROSITE; PS00492; CLUSTERIN_1; 1.
PE 2: Evidence at transcript level;
KW Chaperone; Cytoplasm; Cytoplasmic vesicle; Disulfide bond;
KW Endoplasmic reticulum; Glycoprotein; Membrane; Microsome; Mitochondrion;
KW Nucleus; Phosphoprotein; Reference proteome; Secreted; Signal;
KW Ubl conjugation.
FT SIGNAL 1..22
FT /evidence="ECO:0000250"
FT CHAIN 23..447
FT /note="Clusterin"
FT /id="PRO_0000005541"
FT CHAIN 23..225
FT /note="Clusterin beta chain"
FT /evidence="ECO:0000250"
FT /id="PRO_0000005542"
FT CHAIN 226..447
FT /note="Clusterin alpha chain"
FT /evidence="ECO:0000250"
FT /id="PRO_0000005543"
FT MOTIF 77..80
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q06890"
FT MOTIF 441..445
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q06890"
FT MOD_RES 132
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P10909"
FT MOD_RES 394
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P10909"
FT CARBOHYD 85
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 102
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 144
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 289
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 326
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 352
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 372
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 101..311
FT /note="Interchain (between beta and alpha chains)"
FT /evidence="ECO:0000250"
FT DISULFID 112..303
FT /note="Interchain (between beta and alpha chains)"
FT /evidence="ECO:0000250"
FT DISULFID 115..300
FT /note="Interchain (between beta and alpha chains)"
FT /evidence="ECO:0000250"
FT DISULFID 120..293
FT /note="Interchain (between beta and alpha chains)"
FT /evidence="ECO:0000250"
FT DISULFID 128..283
FT /note="Interchain (between beta and alpha chains)"
FT /evidence="ECO:0000250"
SQ SEQUENCE 447 AA; 51851 MW; C0CA338EEB08590A CRC64;
MKTLLLCVGL LLSWERGQVL GDQLVSDNEL QEMSTQGSKY IDREIQNAVK GVQEIKTLIE
KTNEERKTLL SVLEEAKKNK EDALNETRDS ETKLKAFPEV CNETMMALWE ECKPCLKQTC
MKFYARVCRS GSGLVGRQLE EFLNQSSPFY FWINGDRIDS LLENDRQQSH VLDVMQDSFN
RATGIMDELF QDRFFTHKPQ DTFYHSPFSY FRRPPLHYAK SRLVRNIMPL SLYGPLNFQD
MFQPFFEMIH QAQQAMDVHL HSPAYQTPNV EFITGGPDDR AVCKEIRHNS TGCLRMKDQC
AKCQEILSVD CSANNPSQNQ LRQELNDSLR LAEELTKRYN ELLQSYQWKM LNTSSLLDQP
NEQFNWVSQL ANLTQGPDQY YLRVSTVTSH TSESEAPSRV TEVVVKLFDS DPITITIPEE
VSRDNPKFME TVAEKALQEY RKKKRVE
