Abstract
Hsp90 is a ubiquitous molecular chaperone that interacts with highly diverse protein substrates. Previous structural analysis demonstrated that Hsp90 can adopt a large number of structurally distinct conformations, however the functional role of this flexibility is not understood. We investigate the structural consequences of substrate binding with a model system in which Hsp90 interacts with a constitutively unfolded protein (Δ131Δ), a well-studied fragment of staphylococcal nuclease. SAXS measurements reveal that under apo conditions Hsp90 partially closes around Δ131Δ and in the presence of AMPPNP Δ131Δ binds with increased affinity to Hsp90's fully closed state. Δ131Δ accelerates the nucleotide-driven open/closed transition and stimulates ATP hydrolysis by Hsp90. NMR measurements reveal that Hsp90 binds to a specific region of Δ131Δ. Although Δ131Δ is globally unfolded this particular region is significantly structured. These results indicate that Hsp90 can bind a locally structured region in a globally unfolded protein and this binding drives conformational and functional changes in the chaperone.
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