These results suggest a general mechanism by which Hsp90 can recognize and remodel native proteins by binding and remodeling partially folded states that are transiently sampled from within the native ensemble. In this study, we explored the intrinsic biochemical and molecular properties of AtBAG2 and characterized this protein as a novel molecular chaperone. Moreover, native-state hydrogen exchange indicates that Hsp90 can also interact with partially folded states only transiently populated from within a thermodynamically stable, native-state ensemble. However, information on the biochemical and molecular functions of BAG proteins that affect plant physiology is extremely limited. These findings implicate Hsp90’s conformational dynamics in its ability to bind and remodel partially folded proteins. Cross-linking and NMR measurements indicate that Hsp90 binds to a large partially folded region of the substrate and significantly alters both its local and long-range structure. Using a partially folded protein as a model system, we find that the bacterial Hsp90 adapts its conformation to the substrate, forming a binding site that spans the middle and C-terminal domains of the chaperone. However, critically testing the mechanism of substrate recognition and remodeling by Hsp90 has been challenging. Chemical chaperones are a class of small molecules that function to enhance the folding and/or stability of proteins. Hsp90 is believed to preferentially interact with partially folded substrates, and it has been hypothesized that the chaperone can significantly alter substrate structure as a mechanism to alter the substrate functional state. Hsp90 is a conformationally dynamic molecular chaperone known to promote the folding and activation of a broad array of protein substrates (“clients”). Deputy Director of National Reference Center.
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