The chaperone action of clusterin and its putative role in quality control of extracellular protein folding
The function(s) of clusterin may depend upon its topological location. A variety of intracellular "isoforms" of clusterin have been reported but further work is required to better define their identity. The secreted form of clusterin has a potent ability to inhibit both amorphous and amyloid protein aggregation. In the case of amorphous protein aggregation, clusterin forms stable, soluble high-molecular-weight complexes with misfolded client proteins. Clusterin expression is increased during many types of physiological and pathological stresses and is thought to function as an extracellular chaperone (EC). The pathology of a variety of serious human diseases is thought to arise as a consequence of the inappropriate aggregation of specific extracellular proteins (e.g., A beta peptide in Alzheimer's disease and beta(2)-Microglobulin in dialysis-related amyloidosis). We have proposed that together with other abundant ECs (e.g., haptoglobin and alpha(2)-macroglobulin), clusterin forms part of a previously unknown quality-control (QC) system for protein folding that mediates the recognition and disposal of extracellular misfolded proteins via receptor-mediated endocytosis and lysosomal degradation. Characterizing the mechanisms of this extracellular QC system will thus have major implications for our understanding of diseases of this type and may eventually lead to the development of new therapies. (C) 2009 Elsevier Inc.
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