The client protein p53 forms a molten globule-like state in the presence of Hsp90

It is not currently known in what state (folded, unfolded, alternatively folded) client proteins interact with chaperone Hsp90. We show that one client, the p53 DNA-binding domain, undergoes a structural change in the presence of Hsp90 to adopt a molten globule-like state. Addition of one- and two-domain constructs of Hsp90, as well as the full-length three-domain protein, to isotopically-labeled p53 results in reduction in NMR signal intensity throughout p53, particularly its central β-sheet. This reduction appears to be associated with a change of structure of p53 without formation of a distinct complex with Hsp90. Fluorescence and hydrogen-exchange measurements support a loosening in the structure of p53 in the presence of Hsp90 and its domains. We propose that Hsp90 interacts with p53 by multiple transient interactions, forming a dynamic heterogeneous manifold of conformational states that resembles a molten globule.