Evolutionary epitopes of Hsp90 and p23: implications for their interaction

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Abstract
The amino-terminal domain (N-domain) of Hsp90 represents the ATP binding site and is important for interaction with its cochaperone, p23. Whereas some evidence suggests that p23 may bind to this domain in an ATP-dependent manner and that this process requires the dimerization of two N-domains, the interaction sites between them and the molecular mechanism of coupling these two events to p23 binding remain unsolved. As a first step toward establishing the interaction mechanism, we used the evolutionary tracing (ET) method [Lichtarge, O., Bourne, H. R., and Cohen, F. E. (1996) J. Mol. Biol. 257, 342–358] to identify the putative functional surfaces of Hsp90 and p23, and combined with protein-protein docking techniques, to predict their binding interface. Both evolutionarily privileged surfaces of Hsp90 and p23 identified by ET appear on this putative interface. An analysis of the complex model produced using the ET results combined with available experimental data highlights a putative conformational pathwa...