P25473 · CLUS_CANLF

Function

function

Functions as extracellular chaperone that prevents aggregation of non native proteins. Prevents stress-induced aggregation of blood plasma proteins. Inhibits formation of amyloid fibrils by APP, APOC2, B2M, CALCA, CSN3, SNCA and aggregation-prone LYZ variants (in vitro). Does not require ATP. Maintains partially unfolded proteins in a state appropriate for subsequent refolding by other chaperones, such as HSPA8/HSC70. Does not refold proteins by itself (By similarity).
Binding to cell surface receptors triggers internalization of the chaperone-client complex and subsequent lysosomal or proteasomal degradation (PubMed:11697889).
When secreted, protects cells against apoptosis and against cytolysis by complement. 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. Promotes proteasomal degradation of COMMD1 and IKBKB. Modulates NF-kappa-B transcriptional activity (By similarity).
Following stress, promotes apoptosis (By similarity).
Inhibits apoptosis when associated with the mitochondrial membrane by interference with BAX-dependent release of cytochrome c into the cytoplasm. Plays a role in the regulation of cell proliferation. An intracellular form suppresses stress-induced apoptosis by stabilizing mitochondrial membrane integrity through interaction with HSPA5. Secreted form does not affect caspase or BAX-mediated intrinsic apoptosis and TNF-induced NF-kappa-B-activity (By similarity).
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).

GO annotations

AspectTerm
Cellular Componentchromaffin granule
Cellular Componentcytosol
Cellular Componentendoplasmic reticulum lumen
Cellular Componentextracellular space
Cellular ComponentGolgi apparatus
Cellular Componentmitochondrial inner membrane
Cellular Componentmitochondrion
Cellular Componentnucleus
Cellular Componentperinuclear endoplasmic reticulum lumen
Cellular Componentperinuclear region of cytoplasm
Cellular Componentspherical high-density lipoprotein particle
Molecular Functionmisfolded protein binding
Molecular Functionprotein-folding chaperone binding
Molecular Functionubiquitin protein ligase binding
Molecular Functionunfolded protein binding
Biological Processchaperone-mediated protein folding
Biological Processimmune complex clearance
Biological Processintrinsic apoptotic signaling pathway
Biological Processnegative regulation of amyloid fibril formation
Biological Processnegative regulation of intrinsic apoptotic signaling pathway in response to DNA damage
Biological Processnegative regulation of protein-containing complex assembly
Biological Processpositive regulation of apoptotic process
Biological Processpositive regulation of intrinsic apoptotic signaling pathway
Biological Processpositive regulation of NF-kappaB transcription factor activity
Biological Processpositive regulation of proteasomal ubiquitin-dependent protein catabolic process
Biological Processpositive regulation of receptor-mediated endocytosis
Biological Processpositive regulation of ubiquitin-dependent protein catabolic process
Biological Processprotein stabilization
Biological Processregulation of apoptotic process
Biological Processregulation of cell population proliferation
Biological Processresponse to misfolded protein

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

Gene names

    • Name
      CLU

Organism names

Accessions

  • Primary accession
    P25473

Proteomes

Subcellular Location

Secreted
Nucleus
Cytoplasm
Mitochondrion membrane
; Peripheral membrane protein
Cytoplasm, cytosol
Microsome
Endoplasmic reticulum
Mitochondrion
Note: Can retrotranslocate from the secretory compartments to the cytosol upon cellular stress. Detected in perinuclear foci that may be aggresomes containing misfolded, ubiquitinated proteins. Detected at the mitochondrion membrane upon induction of apoptosis. 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. ER stress reduces secretion. Under the stress, minor amounts of non-secreted forms accumulate in cytoplasm.

Keywords

PTM/Processing

Features

Showing features for signal, chain, glycosylation, disulfide bond, modified residue.

Type
IDPosition(s)Description
Signal1-22
ChainPRO_000000552423-226Clusterin beta chain
ChainPRO_000000552323-445Clusterin
Glycosylation86N-linked (GlcNAc...) asparagine
Disulfide bond102↔309Interchain (between beta and alpha chains)
Glycosylation103N-linked (GlcNAc...) asparagine
Disulfide bond113↔301Interchain (between beta and alpha chains)
Disulfide bond116↔298Interchain (between beta and alpha chains)
Disulfide bond121↔291Interchain (between beta and alpha chains)
Disulfide bond129↔281Interchain (between beta and alpha chains)
Modified residue133Phosphoserine
Glycosylation145N-linked (GlcNAc...) asparagine
ChainPRO_0000005525227-445Clusterin alpha chain
Glycosylation277N-linked (GlcNAc...) asparagine
Glycosylation287N-linked (GlcNAc...) asparagine
Glycosylation350N-linked (GlcNAc...) asparagine
Glycosylation370N-linked (GlcNAc...) asparagine
Modified residue392Phosphoserine

Post-translational modification

Proteolytically cleaved on its way through the secretory system, probably within the Golgi lumen (By similarity) (PubMed:7744793).
Proteolytic cleavage is not necessary for its chaperone activity. All non-secreted forms are not proteolytically cleaved. Chaperone activity of uncleaved forms is dependent on a non-reducing environment (By similarity).
This proteolytic maturation is disulfide bond formation dependent (PubMed:7744793).
Polyubiquitinated, leading to proteasomal degradation. Under cellular stress, the intracellular level of cleaved form is reduced due to proteasomal degradation.
Heavily N-glycosylated. About 30% of the protein mass is comprised of complex N-linked carbohydrate. Endoplasmic reticulum (ER) stress induces changes in glycosylation status and increases level of hypoglycosylated forms. Core carbohydrates are essential for chaperone activity. Non-secreted forms are hypoglycosylated or unglycosylated.

Keywords

Proteomic databases

PTM databases

Expression

Gene expression databases

Interaction

Subunit

Antiparallel disulfide-linked heterodimer of an alpha chain and a beta chain. Self-associates and forms higher oligomers. Interacts with a broad range of misfolded proteins, including APP, APOC2 and LYZ. Slightly acidic pH promotes interaction with misfolded proteins. Forms high-molecular weight oligomers upon interaction with misfolded proteins. Interacts with APOA1, LRP2, CLUAP1 and PON1. Interacts with the complement complex. Interacts (via alpha chain) with XRCC6. Interacts with SYVN1, COMMD1, BTRC, CUL1 and with ubiquitin and SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes. Interacts (via alpha chain) with BAX in stressed cells, where BAX undergoes a conformation change leading to association with the mitochondrial membrane. Does not interact with BAX in unstressed cells. Found in a complex with LTF, CLU, EPPIN and SEMG1. 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. Interacts with BCL2L1; this interaction releases and activates BAX and promotes cell death. Interacts with TGFBR2 and ACVR1 (By similarity).
Interacts (secreted form) with STMN3; this interaction may act as an important modulator during neuronal differentiation (By similarity).
Interacts with VLDLR and LRP8 (By similarity).

Protein-protein interaction databases

Structure

Family & Domains

Features

Showing features for motif.

TypeIDPosition(s)Description
Motif78-81Nuclear localization signal
Motif439-443Nuclear localization signal

Sequence similarities

Belongs to the clusterin family.

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Sequence processing
    The displayed sequence is further processed into a mature form.
  • Length
    445
  • Mass (Da)
    51,790
  • Last updated
    1992-05-01 v1
  • MD5 Checksum
    63A6D0BC4A4CE6C6CDDCC26C0FF732CD
MMKTLLLLVGLLLTWDNGRVLGDQAVSDTELQEMSTEGSKYINKEIKNALKGVKQIKTLIEQTNEERKSLLSNLEEAKKKKEDALNDTKDSETKLKASQGVCNDTMMALWEECKPCLKQTCMKFYARVCRSGSGLVGHQLEEFLNQSSPFYFWMNGDRIDSLLENDRQQTHALDVMQDSFNRASSIMDELFQDRFFTREPQDTYHYSPFSLFQRRPFFNPKFRIARNIIPFPRFQPLNFHDMFQPFFDMIHQAQQAMDVNLHRIPYHFPIEFPEEDNRTVCKEIRHNSTGCLKMKDQCEKCQEILSVDCSSNNPAQVQLRQELSNSLQIAEKFTKLYDELLQSYQEKMFNTSSLLKQLNEQFSWVSQLANLTQSEDPFYLQVTTVGSQTSDSNVPVGFTKVVVKLFDSDPITVMIPEAVSRNNPKFMETVAEKALQEYRQKHREE

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
M55251
EMBL· GenBank· DDBJ
AAA30846.1
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. Our staff consists of biologists and biochemists that are not trained to give medical advice.
This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our Privacy Notice.
Help