![]() Several independent studies have reported unfolding of misfolded polypeptides by chaperonins and Hsp70 chaperones. Here, we focus on chaperones that seem to function as catalytic unfolding enzymes and are of importance in combating early proteotoxic intermediates in protein conformational diseases. For a general review on the main chaperone families, their structures, and their anti-aggregation activities, see. In youth, however, a cellular network composed of molecular chaperones and of chaperone-controlled proteases can efficiently counteract toxic protein aggregation by a mechanism generally termed as “holdase”, corresponding to the non-catalytic tight binding of aggregation-prone misfolding intermediates to the chaperone surface. Moreover, aggregates may be cytotoxic, especially to animal cells, and cause aging-induced degenerative disorders, such as Parkinson’s, Huntington’s and Alzheimer’s diseases. Thus, aggregate-entrapped polypeptides may become precluded from dissociating and reaching their native state within a biologically relevant time-scale. Because of cooperativity, a simple increase in the number of surface-exposed hydrophobic residues may result in a synergic increase of the affinity between several misfolded polypeptides. Yet, the refolding process is often inefficient because hydrophobic residues that in stress-unfolded or de novo-synthesized polypeptides become abnormally exposed to the aqueous phase, may spontaneously seek intra-molecular stability by forming wrong beta sheets and improper inter-molecular ensembles generally called aggregates. Thus, holding and catalytic unfolding chaperones can act as primary cellular defenses against the formation of early misfolded and aggregated proteotoxic conformers in order to avert or retard the onset of degenerative protein conformational diseases.Īnfinsen demonstrated that under optimal non-physiological conditions of low protein concentrations and low temperatures, the primary amino acid sequence of a polypeptide contains the necessary instructions for its spontaneous acquisition of a narrow range of relatively stable but dynamic functional structures, generally referred to as the “native state”. ![]() Whereas during stress, a large excess of non-catalytic chaperones in holding mode may optimally prevent protein aggregation, after the stress, catalytic disaggregases and unfoldases may act as nanomachines that use the energy of ATP hydrolysis to repair proteins with compromised conformations. One unfoldase chaperone may thus successively convert many misfolded or alternatively folded polypeptide substrates into transiently unfolded intermediates, which, once released, can spontaneously refold into low-affinity native products. To carry such physiological functions, major members of the Hsp70, Hsp110, Hsp100, and Hsp60/CCT chaperone families act as catalytic unfolding enzymes or unfoldases that drive iterative cycles of protein binding, unfolding/pulling, and release. Yet, chaperones also carry physiological functions that do not necessitate prevention of aggregation, such as altering the native states of proteins, as in the disassembly of SNARE complexes and clathrin coats. By virtue of their general ability to bind (hold) translocating or unfolding polypeptides otherwise doomed to aggregate, molecular chaperones are commonly dubbed “holdases”.
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