From the cradle to the grave: molecular chaperones that may choose betweenfolding and degradation

Molecular chaperones are known to facilitate cellular protein folding. They bind non-native proteins and orchestrate the folding process in conjunctio n with regulatory cofactors that modulate the affinity of the chaperone for its substrate. However, not every attempt to fold a protein is successful and chaperones can direct misfolded proteins to the cellular degradation ma chinery for destruction. Protein quality control thus appears to involve cl ose cooperation between molecular chaperones and energy-dependent proteases . Molecular mechanisms underlying this interplay have been largely enigmati c so far. Here we present a novel concept for the regulation of the eukaryo tic Hsp70 and Hsp90 chaperone systems during protein folding and protein de gradation.