While it is clear that many unfolded proteins can attain their native state spontaneously in vitro, the efficiency of such folding is usually limited to conditions far removed from those encountered within cells. Two properties of the cellular environment are expected to enhance strongly the propensity of incompletely folded polypeptides to misfold and aggregate: the crowding effect caused by the high concentration of macromolecules, and the close proximity of nascent polypeptide chains emerging from polyribosomes. However, in the living cell, non-productive protein folding is in many, if not most, cases prevented by the action of a highly conserved set of proteins termed molecular chaperones. In the cytoplasm, the Hsp70 (heat-shock protein of 70 kDa) and chaperonin families of molecular chaperones appear to be the major contributors to efficient protein folding during both normal conditions and adverse conditions such as heat stress. Hsp70 chaperones recognize and shield short, hydrophobic peptide segments in the context of non-native polypeptides and probably promote folding by decreasing the concentration of aggregation-prone intermediates. In contrast, the chaperonins interact with and globally enclose collapsed folding intermediates in a central cavity where efficient folding can proceed in a protected environment. For a number of proteins, folding requires the co-ordinated action of both of these molecular chaperones.

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