Chaperones substrate unfolding

Parkin substrates. (B) A model for Parkin-dependent degradation of misfolded proteins. Parkin recruits a complex containing molecular chaperones and the unfolded substrates to the proteasome. Degradation may be facilitated by... 

FIGURE 4-30 Chaperones in protein folding. The cyclic pathway by which chaperones bind and release polypeptides is illustrated for the . coli chaperone proteins DnaK and DnaJ, homologs of the eukaryotic chaperones Hsp70 and Hsp40. The chaperones do not actively promote the folding of the substrate protein, but instead prevent aggregation of unfolded peptides. For a population of polypeptides, some... 

Another structural feature that may facilitate the retrotranslocation of RTA is its inherent ability to adopt metastable conformations in solution (McHugh et al., 2004). In this model, a significant fraction of RTA would transiently adopt a partly unfolded state in which the hydrophobic surfaces of the RTA C-terminal domain are exposed to the ERAD mechanism on dissociation of RTB. The N-terminal domain of RTA, which is more stable in solution than is RTA (Olson et al., 2004), would provide a structural anchor for refolding RTA to the functional 7V-glycosidase conformation, perhaps with the aid of appropriate chaperones. Potential chaperones for refolding in the cytosol include host cell proteins or the rRNA substrate itself (Argent et al., 2000). 

Although much has been learned about the structure and function of Clp chaperones and their role in proteolysis, the mechanism of protein unfolding catalyzed by Clp ATPases and the mechanism of translocation of the unfolded proteins from Clp ATPases to partner proteases remain unsolved puzzles. However, models in which mechanical force is used to destabilize the structure of the substrate in a processive and directional manner are probable. It also seems likely that when ClpA ATPases are associated with proteases, unfolding is coupled to extrusion of the unfolded protein into the proteolytic cavity. In summary, it is anticipated that the large family of Clp ATPases will accomplish their many important cellular functions by similar mechanisms and what has been learned by studying the prokaryotic members reviewed here will shed a great deal of light on all members of the family. 

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