The role of heat-shock and chaperone proteins in protein folding: possible molecular mechanisms

Recently some heat-shock proteins have been linked to functions of 'chaperoning' protein folding in vivo. Here current experimental evidence is reviewed and possible requirements for such an activity are discussed. It is proposed that one mode of chaperone action is to actively unfold misfolded or badly aggregated proteins to a conformation from which they could refold spontaneously; that improperly folded proteins are recognized by excessive stretches of solvent-exposed backbone, rather than by exposed hydrophobic patches; and that the molecular mechanism for unfolding is either repeated binding and dissociation ('plucking') or translocation of the protein backbone through a binding cleft ('threading'), allowing the threaded chain to refold spontaneously. The observed hydrolysis of ATP would provide the energy for active unfolding. These hypotheses can be applied to both monomeric folding and oligomeric assembly and are sufficiently detailed to be open to directed experimental verification.