Small Heat‐shock Proteins and Clusterin: Intra‐ and Extracellular Molecular Chaperones with a Common Mechanism of Action and Function?

Abstract

Small heat-shock proteins (sHsps) and clusterin are molecular chaperones that share many functional similarities despite their lack of significant sequence similarity. These functional similarities, and some differences, are discussed. sHsps are ubiquitous intracellular proteins whereas clusterin is generally found extracellularly. Both chaperones potently prevent the amorphous aggregation and precipitation of target proteins under stress conditions such as elevated temperature, reduction and oxidation. In doing so, they act on the slow off-folding protein pathway. The conformational dynamism and aggregated state of both proteins may be crucial for their chaperone function. Subunit exchange is likely to be important in regulating chaperone action; the dissociated form of the protein is probably the chaperone-active species rather than the aggregated state. They both exert their chaperone action without the need for hydrolysis of ATP and have little ability to refold target proteins. Increased expression of sHsp and clusterin accompanies a range of diseases, e.g. Alzheimer's, Creutzfeldt-Jakob and Parkinson's diseases, that arise from protein misfolding and deposition of highly structured protein aggregates known as amyloid fibrils. The interaction of sHsps and clusterin with fibril-forming species is discussed along with their ability to prevent fibril formation, probably via utilization of their chaperone ability. Disciplines Life Sciences | Physical Sciences and Mathematics | Social and Behavioral Sciences Publication DetailsThis article was originally published as Carver, JA, Rekas, A, Thorn, DC and Wilson, MR, Small heat-shock proteins and clusterin: intra-and extracellular molecular chaperones with a common mechanism of action and function, IUBMB Life, 55, 2003, 661-668 AbstractSmall heat-shock proteins (sHsps) and clusterin are molecular chaperones that share many functional similarities despite their lack of significant sequence similarity. These functional similarities, and some differences, are discussed. sHsps are ubiquitous intracellular proteins whereas clusterin is generally found extracellularly. Both chaperones potently prevent the amorphous aggregation and precipitation of target proteins under stress conditions such as elevated temperature, reduction and oxidation. In doing so, they act on the slow off-folding protein pathway. The conformational dynamism and aggregated state of both proteins may be crucial for their chaperone function. Subunit exchange is likely to be important in regulating chaperone action; the dissociated form of the protein is probably the chaperone-active species rather than the aggregated state. They both exert their chaperone action without the need for hydrolysis of ATP and have little ability to refold target proteins. Increased expression of sHsp and clusterin accompanies a range of diseases, e.g. Alzheimer's, Creutzfeldt-Jakob and Parkinson's diseases, that arise from protein misfolding and deposition of highly structured protein aggregates known as amyloid f...

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

“…CLU mRNA is widely expressed (de Silva et al 1990) and the mature CLU product is secreted out of the cell to serve as an extracellular chaperone (Carver et al 2003;Wyatt et al 2009). Secreted CLU is a heavily glycosylated, 75-80-kDa heterodimeric protein that is linked by five disulfide bonds (Choi-Miura et al 1992).…”

Extracellular Chaperones

“…Since that time many studies have shown that clusterin has chaperone activity similar to that of the small heat-shock proteins (sHsps) [22,23,[26][27][28][29]33]. At substoichiomentric concentrations, clusterin inhibits the stress-induced amorphous aggregation of a large number of unrelated client proteins by binding, in an ATP-independent manner, to areas of exposed hydrophobicity on partially unfolded intermediates [22,[26][27][28][29]31].…”

“…As a result, it is unlikely that detailed X-ray crystal structures of full-length casein protein will be achieved; however, three-dimensional energy-minimized molecular models are available [203,204]. Two of the casein proteins, α S1 -and β-casein, have been found to have molecular chaperone-like activity, similar to the small heat shock proteins (sHsps) [26,92]. The open, flexible nature of α S1 -casein and β-casein results from the high percentage of proline residues in their amino acid sequence (9% of the amino acid sequence of α S1 -casein and 18% of β-casein) and lack of disulfide bonds.…”

“…Both α S1 -casein and β-casein also possess a high degree of overall hydrophobicity, with well separated hydrophilic and hydrophobic domains. Such properties, which they share with other molecular chaperones such as the sHsps and clusterin [26], likely accounts for their ability to bind to a wide-range of destabilized, partially unfolded target proteins to prevent their aggregation [92].…”

“…They do so by forming high molecular weight complexes with the target protein, and stabilizing them in order to prevent their aggregation and potential precipitation. They have no intrinsic re-folding ability [95,96] and thus their mechanism of action is akin to the sHsps and clusterin [26]. The chaperone-like activity of α S -casein and β-casein against amorphously aggregating target proteins is phosphorylation-dependent, dephosphorylation decreasing their chaperone efficacy [94,205].…”