Clusterin

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

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).

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

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 is_associated_with::blood plasma, is_associated_with::milk, is_associated_with::urine, is_associated_with::cerebrospinal fluid and is_associated_with::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 is_associated_with::immunoglobulins, is_associated_with::lipids, is_associated_with::heparin, is_associated_with::bacteria, complement components, is_associated_with::paraoxonase, is_associated_with::beta amyloid, is_associated_with::leptin and others. Clusterin has been ascribed a plethora of functions such as is_associated_with::phagocyte recruitment, aggregation induction, complement attack prevention, is_associated_with::apoptosis inhibition, membrane remodelling, lipid transport, is_associated_with::hormone transport and/or scavenging and is_associated_with::matrix metalloproteinase inhibition.

Clinical associations
Two independent genome-wide association studies found a statistical association between a SNP within the clusterin gene and the risk of having is_associated_with::Alzheimer's disease. Further studies have suggested that people who already have Alzheimer's disease have more clusterin in their blood, and that clusterin levels in blood correlate with faster cognitive decline in individuals with Alzheimer's disease, but have not found that clusterin levels predicted the onset of Alzheimer's disease.

There are two isoforms (1 and 2) with antagonistic actions regarding apoptosis. Clusterin is implicated in a number of biological processes, including lipid transport, membrane recycling, cell adhesion, programmed cell death, and complement cascade, representing a truly multifunctional protein. Isoform 2 is overexpressed under cellular stress conditions and protects cells from apoptosis by impeding Bax actions on the mitochondrial membrane and exerts other protumor activities, like phosphatidylinositol 3-kinase/protein kinase B pathway activation, modulation of extracellular signal-regulated kinase 1/2 signaling and matrix metallopeptidase-9 expression, increased angiogenesis, modulation of the nuclear factor kappa B pathway, among others.