CLUS_PIG
ID CLUS_PIG Reviewed; 446 AA.
AC Q29549;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 120.
DE RecName: Full=Clusterin {ECO:0000303|PubMed:9175781};
DE AltName: Full=CP40 {ECO:0000303|PubMed:9175781};
DE AltName: Full=Complement cytolysis inhibitor {ECO:0000303|PubMed:1544909};
DE Short=CLI {ECO:0000303|PubMed:1544909};
DE Contains:
DE RecName: Full=Clusterin beta chain;
DE Contains:
DE RecName: Full=Clusterin alpha chain;
DE Flags: Precursor;
GN Name=CLU;
OS Sus scrofa (Pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX NCBI_TaxID=9823;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=1544909; DOI=10.1016/s0021-9258(18)42760-3;
RA Diemer V., Hoyle M., Baglioni C., Millis A.J.;
RT "Expression of porcine complement cytolysis inhibitor mRNA in cultured
RT aortic smooth muscle cells. Changes during differentiation in vitro.";
RL J. Biol. Chem. 267:5257-5264(1992).
RN [2]
RP PARTIAL PROTEIN SEQUENCE, AND TISSUE SPECIFICITY.
RX PubMed=9175781; DOI=10.1006/bbrc.1997.6704;
RA Ogawa S., Ishibashi Y., Sakamoto Y., Kitamura K., Kubo M., Sakai T.,
RA Inoue K.;
RT "The glycoproteins that occur in the colloids of senescent porcine
RT pituitary glands are clusterin and glycosylated albumin fragments.";
RL Biochem. Biophys. Res. Commun. 234:712-718(1997).
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 {ECO:0000250|UniProtKB:Q9XSC5}. Note=Can
CC retrotranslocate from the secretory compartments to the cytosol upon
CC cellular stress. Detected in perinuclear foci that may be aggresomes
CC containing misfolded, ubiquitinated proteins. Detected at the
CC mitochondrion membrane upon induction of apoptosis. Under ER stress, a
CC immaturely glycosylated pre-secreted form retrotranslocates from the
CC endoplasmic reticulum (ER)-Golgi network to the cytoplasm to localize
CC in the mitochondria through HSPA5 interaction. ER stress reduces
CC secretion. Under the stress, minor amounts of non-secreted forms
CC accumulate in cytoplasm. {ECO:0000250|UniProtKB:P10909}.
CC -!- TISSUE SPECIFICITY: Highest levels in brain and liver; lower levels are
CC detected in other tissues, including the aorta. Abundant in senescent
CC porcine pituitary colloids. {ECO:0000269|PubMed:9175781}.
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; M84639; AAA31013.1; -; mRNA.
DR PIR; A42108; A42108.
DR RefSeq; NP_999136.1; NM_213971.1.
DR AlphaFoldDB; Q29549; -.
DR SMR; Q29549; -.
DR IntAct; Q29549; 1.
DR STRING; 9823.ENSSSCP00000010325; -.
DR PaxDb; Q29549; -.
DR PeptideAtlas; Q29549; -.
DR PRIDE; Q29549; -.
DR Ensembl; ENSSSCT00005015088; ENSSSCP00005008998; ENSSSCG00005009720.
DR Ensembl; ENSSSCT00005015131; ENSSSCP00005009023; ENSSSCG00005009720.
DR Ensembl; ENSSSCT00005015145; ENSSSCP00005009033; ENSSSCG00005009720.
DR Ensembl; ENSSSCT00005015153; ENSSSCP00005009038; ENSSSCG00005009720.
DR Ensembl; ENSSSCT00065034359; ENSSSCP00065014242; ENSSSCG00065025649.
DR Ensembl; ENSSSCT00065034362; ENSSSCP00065014244; ENSSSCG00065025649.
DR Ensembl; ENSSSCT00065034367; ENSSSCP00065014248; ENSSSCG00065025649.
DR GeneID; 397025; -.
DR KEGG; ssc:397025; -.
DR CTD; 1191; -.
DR eggNOG; ENOG502RBQP; Eukaryota.
DR HOGENOM; CLU_042162_2_0_1; -.
DR InParanoid; Q29549; -.
DR OMA; QGSKYIN; -.
DR Reactome; R-SSC-114608; Platelet degranulation.
DR Reactome; R-SSC-166665; Terminal pathway of complement.
DR Reactome; R-SSC-977606; Regulation of Complement cascade.
DR Proteomes; UP000008227; Unplaced.
DR Proteomes; UP000314985; Unplaced.
DR Genevisible; Q29549; SS.
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:0042981; P:regulation of apoptotic process; IBA:GO_Central.
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.
DR PROSITE; PS00493; CLUSTERIN_2; 1.
PE 1: Evidence at protein level;
KW Chaperone; Cytoplasm; Cytoplasmic vesicle; Direct protein sequencing;
KW Disulfide bond; Endoplasmic reticulum; Glycoprotein; Membrane; Microsome;
KW Mitochondrion; Nucleus; Phosphoprotein; Reference proteome; Secreted;
KW Signal; Ubl conjugation.
FT SIGNAL 1..28
FT /evidence="ECO:0000250"
FT CHAIN 29..446
FT /note="Clusterin"
FT /id="PRO_0000005538"
FT CHAIN 29..227
FT /note="Clusterin beta chain"
FT /id="PRO_0000005539"
FT CHAIN 228..446
FT /note="Clusterin alpha chain"
FT /id="PRO_0000005540"
FT MOTIF 78..81
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q06890"
FT MOTIF 440..444
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q06890"
FT MOD_RES 133
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P10909"
FT CARBOHYD 86
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 103
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 145
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 290
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 316
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 353
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 373
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 102..312
FT /note="Interchain (between beta and alpha chains)"
FT /evidence="ECO:0000250"
FT DISULFID 113..304
FT /note="Interchain (between beta and alpha chains)"
FT /evidence="ECO:0000250"
FT DISULFID 116..301
FT /note="Interchain (between beta and alpha chains)"
FT /evidence="ECO:0000250"
FT DISULFID 121..294
FT /note="Interchain (between beta and alpha chains)"
FT /evidence="ECO:0000250"
FT DISULFID 129..284
FT /note="Interchain (between beta and alpha chains)"
FT /evidence="ECO:0000250"
SQ SEQUENCE 446 AA; 51775 MW; B1D5B434B668E3AA CRC64;
MKTLLLLVGL LLTWENGPWV LGDKAISDKE LQEMSTEGSK YVNKEIKNAL KEVKQIKTLI
EQSNEERKSL LSSLEEAKKK KEDALNDTRD TETKLKGSQG LCNETMMALW EECKPCLKQT
CMKFYARVCR SGSGLVGHQL EEFLNQSSPF YFWINGDRID SLMENDRQQS HVMDIMEDSF
NRASNIMDEL FQDRFFNREP FDTQFFSPFG SSHRGSLFFN PKSRFARNIM PFPLFTDLNY
HDMFQPFFDM IHQAQQAMDA HLHRIPYHFP EAGVPENSND RAVCKEIRHN STGCLRMKDQ
CEKCREILSV DCSASNSSQM QLRQELYTSL QMAEKFSKLY DQLLQSYQQK MLNTSSLLKQ
LNEQFSWVSQ LANLTQNDDR YYLQVTTVNS HGSDPSVPSG LTKVVVKLFD SYPITLIIPQ
EVSDPKFMET VAEEALQQYR QRSREE
