Understanding the molecular mechanism of Hsp90: The role of nucleotide hydrolysis in the chaperone cycle

BIOT 48

Kristin A. Krukenberg, kkruken@msg.ucsf.edu, Program in Chemistry and Chemical Biology, University of California, San Francisco, 600 16th St, GH, MC 2280, San Francisco, CA 94158-2517, Friedrich Foerster, Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th St, Byers Hall, MC 2552, San Francisco, CA 94158-2330, Andrej Sali, Department of Biopharmaceutical Sciences, University of California, San Francisco, 1700 4th St, Byers Hall, MC 2552, San Francisco, CA 94158-2330, and David A. Agard, agard@msg.ucsf.edu, Howard Hughes Medical Institute and Department of Biochemistry and Biophysics, University of California, San Francisco, 600 16th St, MC2240, San Francisco, CA 94158-2517.
Hsp90 is an essential eukaryotic chaperone whose function requires the ATPase activity of the N-terminal domain. Crystal structures of the bacterial Hsp90 homolog htpG (Shaiu et al, Cell, 2006) and the yeast Hsp90 (Ali et al, Nature, 2006) reveal large domain rearrangements between the nucleotide-free and the nucleotide-bound conformations, giving insight into the possible mechanisms of Hsp90 function. However, new questions are also raised. What conformations are present in solution, and how do these structural reorganizations relate to Hsp90 function? To answer these questions we are investigating the structure of htpG in solution using small angle X-ray scattering (SAXS). Using SAXS and newly developed molecular modeling methods, we determined novel conformations of htpG in solution, and demonstrated that multiple conformations are in equilibrium. These results provide important new insights into the role of nucleotide in modulating Hsp90 conformation and have important implications for the molecular mechanism and regulation of Hsp90.
 

Biophysical and Biomolecular Symposium: Protein Folding & Characterization
2:00 PM-4:15 PM, Sunday, August 19, 2007 BCEC -- 106, Oral

Division of Biochemical Technology

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007