Clusterin

Clusterin
Clusterin
Identifiers
Symbols CLU; APOJ; CLI; KUB1; MGC24903; SGP-2; SGP2; SP-40; TRPM-2; TRPM2
External IDs OMIM185430 MGI88423 HomoloGene1382 GeneCards: CLU Gene
Orthologs
Species Human Mouse
Entrez 1191 12759
Ensembl ENSG00000120885 ENSMUSG00000022037
UniProt P10909 Q06890
RefSeq (mRNA) NM_001171138.1 NM_013492.2
RefSeq (protein) NP_001164609.1 NP_038520.2
Location (UCSC) Chr 8:
27.45 – 27.47 Mb
Chr 14:
66.59 – 66.6 Mb
PubMed search [1] [2]

Clusterin (apolipoprotein J) is a 75 - 80 kDa disulfide-linked heterodimeric protein associated with the clearance of cellular debris and apoptosis.[1] In humans, clusterin is encoded by the CLU gene.[2]

This protein has several synonyms: dimeric acidic glycoprotein (DAG protein), testosterone repressed prostate message-2 (TRPM-2), sulfated glycoprotein-2 (SGP-2) and complement lysis inhibitor (CLI).

Contents

Genomics

Clusterin was first identified in ram rete testis fluid where it showed signs of clustering with rat sertoli cells and erthrocytes, hence its name. [3]

In humans the gene is encoded on chromosome 8 (8p21) and is highly conserved between species (70-80% homology). It is expressed in most mammalian tissues and can be found in blood plasma, milk, urine, cerebrospinal fluid and semen. A number of proteins have been found to affect its expression including Egr-1, members from the AP-1 complex, HSF1/2, Cdx1/2 and B-Myb.

Molecular biology

The protein itself is a disulfide-linked heterodimeric protein containing about 30% of N-linked carbohydrate rich in sialic acid. Truncated forms targeted to the nucleus have also been identified. The precursor polypeptide chain is cleaved proteolytically to remove the 22 amino acid secretory signal peptide and subsequently between residues 227/228 to generate the alpha and beta chains. These are assembled in an anti-parallel fashion to give a heterodimeric molecule in which the cysteine-rich centers are linked by five disulfide bridges and are flanked by two predicted coiled-coil alpha-helices and three predicted amphipathic alpha-helices.

The mature protein appears as a ≈40 kDa smear on immunoblots from reducing SDS-PAGE. The precursor form appears as a 60 kDa protein.

The protein has been implicated in a variety of activities including programmed cell death, regulation of complement mediated cell lysis, membrane recycling, cell-cell adhesion and src induced transformation. As a part of the attack complex of complement, it acts as a complement inhibitor.

It is able to bind and form complexes with numerous partners such as immunoglobulins, lipids, heparin, bacteria, complement components, paraoxonase, beta amyloid, leptin and others. Clusterin has been ascribed a plethora of functions such as phagocyte recruitment, aggregation induction, complement attack prevention, apoptosis inhibition, membrane remodelling, lipid transport, hormone transport and/or scavenging and matrix metalloproteinase inhibition.

Clinical associations

A recent genome-wide association study[4][5] found a statistical association between a SNP within the clusterin gene and the risk of having Alzheimer's disease. Further studies have suggested that people who already have Alzheimer's disease have more clusterin in their blood[6], and that clusterin levels in blood correlate with faster cognitive decline in individuals with Alzheimer's disease[7], but have not found that clusterin levels predicted the onset of Alzheimer's disease.

References

  1. ^ Jones SE, Jomary C (May 2002). "Clusterin". Int. J. Biochem. Cell Biol. 34 (5): 427–431. doi:10.1016/S1357-2725(01)00155-8. PMID 11906815. 
  2. ^ "Entrez Gene: clusterin". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1191. 
  3. ^ Fritz IB, Burdzy K, Sétchell B, Blaschuk O (June 1983). "Ram rete testis fluid contains a protein (clusterin) which influences cell-cell interactions in vitro". Biol. Reprod. 28 (5): 1173–1188. doi:10.1095/biolreprod28.5.1173. PMID 6871313. 
  4. ^ Harold D, Abraham R, Hollingworth P et al. (September 2009). "Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease". Nat. Genet. 41 (10): 1088–1093. doi:10.1038/ng.440. PMC 2845877. PMID 19734902. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2845877. Lay summary – TIME Magazine (2009-09-06). 
  5. ^ Lambert JC, Heath S, Even G et al. (September 2009). "Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease". Nat. Genet. 41 (10): 1094–1099. doi:10.1038/ng.439. PMID 19734903. 
  6. ^ Schrijvers EM et al. (September 2011). "Plasma clusterin and the risk of Alzheimer disease". JAMA 305 (13): 1322–1326. doi:10.1001/jama.2011.381. PMID 21467285. 
  7. ^ "Plasma Protein Appears to Be Associated With Development and Severity of Alzheimer's Disease". 2010. http://www.sciencedaily.com/releases/2010/07/100705190536.htm#. 

Further reading

External links



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