CLUS_CANLF
ID CLUS_CANLF Reviewed; 445 AA.
AC P25473;
DT 01-MAY-1992, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1992, sequence version 1.
DT 03-AUG-2022, entry version 125.
DE RecName: Full=Clusterin;
DE AltName: Full=Glycoprotein 80 {ECO:0000303|PubMed:2033078};
DE Short=Gp80 {ECO:0000303|PubMed:2033078};
DE Contains:
DE RecName: Full=Clusterin beta chain;
DE Contains:
DE RecName: Full=Clusterin alpha chain;
DE Flags: Precursor;
GN Name=CLU;
OS Canis lupus familiaris (Dog) (Canis familiaris).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae; Canis.
OX NCBI_TaxID=9615;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Cocker spaniel; TISSUE=Kidney;
RX PubMed=2033078; DOI=10.1016/s0021-9258(18)92907-8;
RA Hartmann K., Rauch J., Urban J., Parczyk K., Diel P., Pilarsky C.,
RA Appel D., Haase W., Mann K., Weller A., Koch-Brandt C.;
RT "Molecular cloning of gp 80, a glycoprotein complex secreted by kidney
RT cells in vitro and in vivo. A link to the reproductive system and to the
RT complement cascade.";
RL J. Biol. Chem. 266:9924-9931(1991).
RN [2]
RP PROTEOLYTIC MATURATION.
RX PubMed=7744793; DOI=10.1074/jbc.270.19.11543;
RA Loesch A., Koch-Brandt C.;
RT "Dithiothreitol treatment of Madin-Darby canine kidney cells reversibly
RT blocks export from the endoplasmic reticulum but does not affect vectorial
RT targeting of secretory proteins.";
RL J. Biol. Chem. 270:11543-11548(1995).
RN [3]
RP FUNCTION.
RX PubMed=11697889; DOI=10.1006/excr.2001.5358;
RA Bartl M.M., Luckenbach T., Bergner O., Ullrich O., Koch-Brandt C.;
RT "Multiple receptors mediate apoJ-dependent clearance of cellular debris
RT into nonprofessional phagocytes.";
RL Exp. Cell Res. 271:130-141(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 (By similarity).
CC Binding to cell surface receptors triggers internalization of the
CC chaperone-client complex and subsequent lysosomal or proteasomal
CC degradation (PubMed:11697889). When secreted, protects cells against
CC apoptosis and against cytolysis by complement. Intracellular forms
CC interact with ubiquitin and SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-
CC protein ligase complexes and promote the ubiquitination and subsequent
CC proteasomal degradation of target proteins. Promotes proteasomal
CC degradation of COMMD1 and IKBKB. Modulates NF-kappa-B transcriptional
CC activity (By similarity). Following stress, promotes apoptosis (By
CC similarity). Inhibits apoptosis when associated with the mitochondrial
CC membrane by interference with BAX-dependent release of cytochrome c
CC into the cytoplasm. Plays a role in the regulation of cell
CC proliferation. An intracellular form suppresses stress-induced
CC apoptosis by stabilizing mitochondrial membrane integrity through
CC interaction with HSPA5. Secreted form does not affect caspase or BAX-
CC mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity (By
CC similarity). Secreted form act as an important modulator during
CC neuronal differentiation through interaction with STMN3 (By
CC similarity). Plays a role in the clearance of immune complexes that
CC arise during cell injury (By similarity).
CC {ECO:0000250|UniProtKB:P05371, ECO:0000250|UniProtKB:P10909,
CC ECO:0000250|UniProtKB:Q06890, ECO:0000269|PubMed:11697889}.
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 -!- PTM: Proteolytically cleaved on its way through the secretory system,
CC probably within the Golgi lumen (By similarity) (PubMed:7744793).
CC Proteolytic cleavage is not necessary for its chaperone activity. All
CC non-secreted forms are not proteolytically cleaved. Chaperone activity
CC of uncleaved forms is dependent on a non-reducing envoronment (By
CC similarity). This proteolytic maturation is disulfide bond formation
CC dependent (PubMed:7744793). {ECO:0000250|UniProtKB:P10909,
CC ECO:0000269|PubMed:7744793}.
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; M55251; AAA30846.1; -; mRNA.
DR PIR; A40018; A40018.
DR RefSeq; NP_001003370.1; NM_001003370.1.
DR AlphaFoldDB; P25473; -.
DR SMR; P25473; -.
DR STRING; 9612.ENSCAFP00000012350; -.
DR PaxDb; P25473; -.
DR PRIDE; P25473; -.
DR Ensembl; ENSCAFT00040032862; ENSCAFP00040028589; ENSCAFG00040017797.
DR GeneID; 442971; -.
DR KEGG; cfa:442971; -.
DR CTD; 1191; -.
DR eggNOG; ENOG502RBQP; Eukaryota.
DR HOGENOM; CLU_042162_2_0_1; -.
DR InParanoid; P25473; -.
DR OrthoDB; 973835at2759; -.
DR Reactome; R-CFA-114608; Platelet degranulation.
DR Reactome; R-CFA-166665; Terminal pathway of complement.
DR Reactome; R-CFA-977606; Regulation of Complement cascade.
DR Proteomes; UP000002254; Unplaced.
DR Bgee; ENSCAFG00000008404; Expressed in thyroid gland and 44 other tissues.
DR GO; GO:0042583; C:chromaffin granule; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:ParkinsonsUK-UCL.
DR GO; GO:0005615; C:extracellular space; ISS:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:ParkinsonsUK-UCL.
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:0051087; F:chaperone binding; IPI:ParkinsonsUK-UCL.
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; IMP: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 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:0000255"
FT CHAIN 23..445
FT /note="Clusterin"
FT /id="PRO_0000005523"
FT CHAIN 23..226
FT /note="Clusterin beta chain"
FT /id="PRO_0000005524"
FT CHAIN 227..445
FT /note="Clusterin alpha chain"
FT /id="PRO_0000005525"
FT MOTIF 78..81
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q06890"
FT MOTIF 439..443
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 MOD_RES 392
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 277
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 287
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 350
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 370
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 102..309
FT /note="Interchain (between beta and alpha chains)"
FT /evidence="ECO:0000250"
FT DISULFID 113..301
FT /note="Interchain (between beta and alpha chains)"
FT /evidence="ECO:0000250"
FT DISULFID 116..298
FT /note="Interchain (between beta and alpha chains)"
FT /evidence="ECO:0000250"
FT DISULFID 121..291
FT /note="Interchain (between beta and alpha chains)"
FT /evidence="ECO:0000250"
FT DISULFID 129..281
FT /note="Interchain (between beta and alpha chains)"
FT /evidence="ECO:0000250"
SQ SEQUENCE 445 AA; 51790 MW; 023A37266ABEF374 CRC64;
MMKTLLLLVG LLLTWDNGRV LGDQAVSDTE LQEMSTEGSK YINKEIKNAL KGVKQIKTLI
EQTNEERKSL LSNLEEAKKK KEDALNDTKD SETKLKASQG VCNDTMMALW EECKPCLKQT
CMKFYARVCR SGSGLVGHQL EEFLNQSSPF YFWMNGDRID SLLENDRQQT HALDVMQDSF
NRASSIMDEL FQDRFFTREP QDTYHYSPFS LFQRRPFFNP KFRIARNIIP FPRFQPLNFH
DMFQPFFDMI HQAQQAMDVN LHRIPYHFPI EFPEEDNRTV CKEIRHNSTG CLKMKDQCEK
CQEILSVDCS SNNPAQVQLR QELSNSLQIA EKFTKLYDEL LQSYQEKMFN TSSLLKQLNE
QFSWVSQLAN LTQSEDPFYL QVTTVGSQTS DSNVPVGFTK VVVKLFDSDP ITVMIPEAVS
RNNPKFMETV AEKALQEYRQ KHREE
