Protein Folding and Misfolding in the Eukaryotic Cytosol

Abstract

Molecular chaperones are required for the correct folding and assembly of cellular proteins. Because unfolded or partially folded polypeptide chains are known to have a strong tendency to aggregate, the high density of folding nascent chains emerging from polysomes requires that the growing polypeptide is effectively prevented from misfolding and aggregating, until a chain length suitable for productive folding has been synthesized. Molecular chaperones play an important role in this process. In the eukaryotic cytosol, a network of ribosome‐associated chaperones creates a protected folding environment that sequesters folding intermediates from the bulk cytosol and facilitates folding of the emerging nascent chains. These include Hsp70 family members as well as the ring‐shaped chaperonin TRiC/CCT and the prefoldin/GIMc complex. Molecular chaperones also play an important role preventing aggregation and targeting misfolded proteins for degradation. The mechanism of action and relative contribution of these chaperones to cellular folding and misfolding will be discussed.