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All life is dependent upon protein function, which in turn depends on the maintenance of proteins in their normal (native) shapes. Complex quality control (QC) mechanisms, including molecular chaperones and the proteasome, are known to maintain the native fold and function of intracellular proteins; however, almost nothing is currently known about the mechanisms of extracellular protein QC.
In order to prevent inappropriate extracellular aggregation and deposition of proteins, and to preserve normal physiological functions, it is likely that one or more protein QC mechanisms operate in extracellular body spaces. The capacity of these yet to be identified systems is probably exceeded in human diseases in which extracellular protein aggregation/ deposition is associated with pathology. For example, in autoimmune diseases, circulating immune complexes accumulate in the kidney, joints and elsewhere and give rise to inflammatory responses.
There is also a large family of diseases (the Protein Conformational Disorders; e.g. Alzheimer's disease, prion diseases, Type II diabetes) in which proteins partially unfold in response to mutations, or physical or chemical stresses, and form pathological extracellular aggregates.
Clusterin is arguably the first established abundant human extracellular chaperone (EC). We have produced evidence that clusterin sequesters misfolded extracellular proteins by binding to them to form soluble complexes and then facilitates their disposal via receptor-mediated endocytosis and lysosomal degradation. We hypothesise that this may be a primary QC mechanism for the folding of extracellular proteins effected by clusterin and other abundant ECs.
We are also investigating the possibility that ECs may facilitate the disposal of unfolded/misfolded extracellular proteins via a specific extracellular proteolysis system. Discovering and understanding QC mechanisms for extracellular proteins is important because an awareness of these mechanisms will aid the development of therapies for many important diseases.
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