Background of Clusterin
The mature form of human secreted clusterin (CLU) is a secreted heterodimeric glycoprotein of 75-80 kDa. As other secreted proteins, translation of CLU mRNA results in a preprotein composed of 449 amino acids (psCLU). The psCLU is transported into the Golgi and then heavily glycosylated. A proteolysis process removes the leader signal polypeptide and cleaves the preprotein into an α-chain and a β-chain. The two chains are linked in an antiparallel fashion through five disulfide bonds.
Table1 The physicochemical properties of the mature protein
|
Subunit
|
α-chain
|
β-chain
|
|
pI
|
5.25
|
5.88
|
|
Amino acid number
|
228-449
|
23-227
|
|
Mr (K) Predicted
|
26.7
|
24.4
|
|
Mr (K) Observed
|
35-40
|
35-40
|
|
N-linked glycosylation sites
|
4 (291, 317, 354, 374)
|
3 (86, 103, 145)
|
|
Interchain disulphide bonds (5)
|
313, 305, 302, 295, 285
|
102, 113, 116, 121, 129
|
Clusterin Structure
Structural predictions performed in rat, human, and bovine CLU showed highly conserved amphipathic α-helices regions with hydrophobic and hydrophilic features. Intrinsically disordered regions have been also predicted, such as coil-like and molten globule-like regions. These domains are predominantly located at the N- and C- termini of the α- and β-chains. Predicted ordered regions have been found around the conserved cysteine residues implicated in the formation of the five disulfide bonds. A short disordered region comprises the posttranslational cleavage site generating α- and β-chains. The structure of CLU is supposed to be highly flexible, due to the presence of amphipathic α-helix ordered structures and disordered regions. This feature may account for its strong binding activity of unfolded proteins, and/or other putative partners. In fact, CLU forms oligomers, and it can interact with distinct ligands forming complexes with different molecular mass and diameter.
Fig. 1 Clusterin gene and protein structure.1
Clusterin Function
Although CLU was identified more than 30 years ago, an understanding of its biological functions is still elusive. Data showed that CLU inhibits the activity of the complement system. CLU binds to the terminal C complexes and prevents their insertion into cell membranes. The resulting complexes are soluble and unable to induce complement lysis. CLU specifically binds to C7, the β-subunit of C8 and C9. The conformational changes occurring during the formation of MAC expose the interaction sites for CLU that binds to a structural motif common to C7, C8 and C9β inhibiting the correct complex assembly.
It has been speculated that one of CLU in vivo function is to control terminal complement-mediated damage, preventing uncontrolled membrane attack complex (MAC) activity. CLU has been found on MAC bound to circulating immune complexes (CIC) in systemic lupus erythematosus patients. The presence of CLU has been associated with a protective function from complement-mediated injury or from potentially damaging agents of the extracellular environment. The association between CLU and complement proteins has been reported in different human pathological conditions suggesting a protective effect of CLU under stress conditions.
Clusterin Tissue Distribution
CLU is ubiquitously expressed in almost all mammalian tissues and has been found in all human body fluids and analyzed. CLU circulates in human plasma at a concentration of 150-540 μg/mL. It is about 10 times higher in human seminal plasma. In plasma, CLU is a soluble protein or a component of a lipid-poor subclass of high-density lipoproteins of 70-200 kDa. Under stress conditions, CLU may escape the canonical pathway of secretory proteins, and the different forms that are originated from altered biogenesis may localize in various intracellular compartments such as cytoplasm, mitochondria, microsomes, nuclei, and cell membranes.
Creative Biolabs is committed to providing high-quality complement component-related services and products. If you are interested in our services, please directly contact us and consult our technical supports for more details.
Reference
-
Foster, Evangeline M., et al. "Clusterin in Alzheimer’s disease: mechanisms, genetics, and lessons from other pathologies." Frontiers in neuroscience 13 (2019): 164.
Related Product
For Research Use Only.
Related Sections:
