Bound for Observation

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Journal of Molecular Biology (Impact Factor: 4.33). 11/2011; 415(1):1-2. DOI: 10.1016/j.jmb.2011.11.004
Source: PubMed
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    ABSTRACT: The molecular chaperone heat-shock protein 90 (Hsp90) couples ATP hydrolysis to conformational changes driving a reaction cycle that is required for substrate activation. Recent structural analysis provided snapshots of the open and closed states of Hsp90, which mark the starting and end points of these changes. Using fluorescence resonance energy transfer (FRET), we dissected the cycle kinetically and identified the intermediates on the pathway. The conformational transitions are orders of magnitude slower than the ATP-hydrolysis step and thus are the limiting events during the reaction cycle. Furthermore, these structural changes can be tightly regulated by cochaperones, being completely inhibited by Sti1 or accelerated by Aha1. In fact, even in the absence of nucleotide, Aha1 induces Hsp90 rearrangements that speed up the conformational cycle. This comprehensive reconstitution of the Hsp90 cycle defines a controlled progression through distinct intermediates that can be modulated by conformation-sensitive cochaperones.
    Nature Structural & Molecular Biology 03/2009; 16(3):287-93. DOI:10.1038/nsmb.1565 · 13.31 Impact Factor
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    ABSTRACT: How can species remain unaltered for long periods yet also undergo rapid diversification? By linking genetic variation to phenotypic variation via environmental stress, the Hsp90 protein-folding reservoir might promote both stasis and change. However, the nature and adaptive value of Hsp90-contingent traits remain uncertain. In ecologically and genetically diverse yeasts, we find such traits to be both common and frequently adaptive. Most are based on preexisting variation, with causative polymorphisms occurring in coding and regulatory sequences alike. A common temperature stress alters phenotypes similarly. Both selective inhibition of Hsp90 and temperature stress increase correlations between genotype and phenotype. This system broadly determines the adaptive value of standing genetic variation and, in so doing, has influenced the evolution of current genomes.
    Science 12/2010; 330(6012):1820-4. DOI:10.1126/science.1195487 · 33.61 Impact Factor
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    ABSTRACT: The Hsp90 molecular chaperone system is involved in the activation of an important set of cell regulatory proteins, including many whose disregulation drives cancer. Recruitment of protein kinases to the Hsp90 system is mediated by the co-chaperone adaptor Cdc37 -- an essential protein whose overexpression is itself, oncogenic. Current structural, biochemical and biological studies of Cdc37 are beginning to unravel the nature of its interactions with Hsp90 and protein kinase clients, and implicate it as a key permissive factor in cell transformation by disregulated protein kinases. The central role of the Hsp90-Cdc37 chaperone complex makes it an important target for future anti-cancer drug development.
    Current Opinion in Genetics & Development 03/2005; 15(1):55-61. DOI:10.1016/j.gde.2004.12.011 · 7.57 Impact Factor
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