Roles of molecular chaperones in protein degradation

H EAT and other forms of stress that cause proteins to denature induce the synthesis of several classes of proteins known as heat shock proteins ( h s p s ) 1 many of which act as molecular chaperones (see Table I). A major role of these molecular chaperones after stress is to catalyze the refolding of denatured proteins (3, 4, 16). However, certain molecular chaperones are produced constitutively indicating that they have important functions even under normal conditions. Such functions are being intensively investigated and include: (a) promotion of proper protein folding after synthesis; (b) stimulation of assembly and disassembly of multimeric proteins; and (c) facilitation of protein translocation across a variety of intracellular membranes including those of the endoplasmic reticulum, mitochondrion, nucleus, and peroxisome (3, 4, 16). Molecular chaperones also stimulate the breakdown of proteins, and the idea has emerged that when molecular chaperones fail in their functions of protein folding, assembly, or translocation, they then facilitate the degradation of the mishandled protein (4, 17). Although this "refold or degrade" model remains to be critically tested, it now appears that molecular chaperones facilitate protein degradation in many different ways. We will cite examples where molecular chaperones increase the susceptibility of certain substrate proteins to proteolytic attack. In some cases the molecular chaperones simply prevent substrate proteins from forming massive aggregates that are partially shielded from proteolytic attack, but in other cases they function in more specific targeting of substrate proteins to particular proteolytic pathways. In addition to these effects on protein substrates, molecular chaperones can increase the overall activities of certain proteolytic pathways. In some cases the molecular chaperones are physically associated with proteases while in other cases they appear to be required for the interactions between different macromolecules needed for the proteolytic pathway to operate efficiently.