TAILIEUCHUNG - Báo cáo khoa học: A common conformationally coupled ATPase mechanism for yeast and human cytoplasmic HSP90s

The conformationally coupled mechanism by which ATP is utilized by yeast Hsp90 is now well characterized. In contrast, ATP utilization by human Hsp90s is less well studied, and appears to operate differently. To resolve these conflicting models, we have conducted a side-by-side biochem-ical analysis in a series of mutant yeast and human Hsp90s that have been both mechanistically and structurally characterized with regard to the crys-tal structure of the yeast Hsp90 protein. | ỊFEBS Journal A common conformationally coupled ATPase mechanism for yeast and human cytoplasmic HSP90S Cara K. Vaughan1 Peter W. Piper2 Laurence H. Pearl1 and Chrisostomos Prodromou1 1 Section of StructuralBiology The Institute of Cancer Research Chester Beatty Laboratories London UK 2 Department of Molecular Biology and Biotechnology The University of Sheffield UK Keywords ATPase activity chaperone heat shock protein Hsp90 N-terminaldimerization Correspondence C. Prodromou Section of StructuralBiology The Institute of Cancer Research Chester Beatty Laboratories 237 Fulham Road London SW3 6JB UK Fax 44 207 153 5457 Tel 44 207 153 5449 E-mail Re-use of this article is permitted in accordance with the Creative Commons Deed Attribution which does not permit commercial exploitation Received 13 June 2008 revised 29 October 2008 accepted 30 October 2008 doi The conformationally coupled mechanism by which ATP is utilized by yeast Hsp90 is now well characterized. In contrast ATP utilization by human Hsp90s is less well studied and appears to operate differently. To resolve these conflicting models we have conducted a side-by-side biochemical analysis in a series of mutant yeast and human Hsp90s that have been both mechanistically and structurally characterized with regard to the crystal structure of the yeast Hsp90 protein. We show that each monomer of the human Hsp90 dimer is mutually dependent on the other for ATPase activity. Fluorescence studies confirmed that the N-terminal domains of Hsp90b come into close association with each other. Mutations that directly affect the conformational dynamics of the ATP-lid segment had marked effects with T31I yeast T22I and A116N yeast A107N stimulating and T110I yeast T101I inhibiting human and yeast ATPase activity to similar extents showing that ATP-dependent lid closure is a key ratedetermining step in both systems. Mutation of residues implicated in N-ter-minal .

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