Protein quality control: triage by chaperones and proteases.

Proteases and chaperones together serve to maintain quahty control of cellular proteins. Both types of en­ zymes have as their substrates the variety of misfolded and partially folded proteins that arise from slow rates of folding or assembly, chemical or thermal stress, intrinsic structural instability, and biosynthetic errors. The pri­ mary function of classical chaperones, such as the Esch­ erichia coh DnaK/Hsp70 and its cochaperones, DnaJ and GrpE, and GroEL/Hsp60 and its cochaperone, GroES, is to modulate protein folding pathways, thereby prevent­ ing misfolding and aggregation, promoting refolding and proper assembly. Recent work has demonstrated that ATP-dependent proteases, as well as closely related pro­ teins, have intrinsic chaperone activity, suggesting that the initial steps in energy-dependent protein degradation may be similar to those of chaperone-dependent protein folding. The classical chaperones are also required for degradation of certain proteins in vivo, but we propose below that generally they affect proteolysis indirectly by maintaining proteins in soluble forms that would other­ wise aggregate and become inaccessible to proteases. In this review we present the evidence linking the activi­ ties of chaperones and proteases, and propose a general model for what can be thought of as a triage system for handling misfolded proteins in vivo, assuring swift re­ folding of proteins with functional potential and rapid degradation of irreversibly denatured or damaged pro­ teins.