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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
 
 
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