Clusterin
Encyclopedia
Clusterin is a 75 - 80 kDa disulfide-linked heterodimeric protein
associated with the clearance of cellular debris and apoptosis
. In humans, clusterin is encoded by the CLU 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).
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.
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, lipid
s, 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.
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, 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.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
associated with the clearance of cellular debris and apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. In humans, clusterin is encoded by the CLU gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
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 erthrocytes, 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 blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
, milk
Milk
Milk is a white liquid produced by the mammary glands of mammals. It is the primary source of nutrition for young mammals before they are able to digest other types of food. Early-lactation milk contains colostrum, which carries the mother's antibodies to the baby and can reduce the risk of many...
, urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
, cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
and semen
Semen
Semen is an organic fluid, also known as seminal fluid, that may contain spermatozoa. It is secreted by the gonads and other sexual organs of male or hermaphroditic animals and can fertilize female ova...
. 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, lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
s, heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
, bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
, complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
components, paraoxonase
Paraoxonase
Paraoxonases are a group of enzymes involved in the hydrolysis of organophosphates.-History:PON was identified as an enzyme having organophosphates as its substrates. Reports of the geographic differences in population frequencies of paraoxonase activity and genetic analysis led to uncovering the...
, beta amyloid, leptin
Leptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...
and others. Clusterin has been ascribed a plethora of functions such as phagocyte
Phagocyte
Phagocytes are the white blood cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are...
recruitment, aggregation induction, complement attack prevention, apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
inhibition, membrane remodelling, lipid transport, hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
transport and/or scavenging and matrix metalloproteinase
Matrix metalloproteinase
Matrix metalloproteinases are zinc-dependent endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily....
inhibition.
Clinical associations
A recent genome-wide association studyGenome-wide association study
In genetic epidemiology, a genome-wide association study , also known as whole genome association study , is an examination of many common genetic variants in different individuals to see if any variant is associated with a trait...
found a statistical association between a SNP within the clusterin gene and the risk of having Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
. 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.