Mechanisms of client protein activation, regulation and targeted destruction by the Hsp90 molecular chaperone system. (360G-Wellcome-080041_Z_06_Z)
The Hsp90 molecular chaperone system is involved in the activation of an important set of cell regulatory proteins, including many oncogenic protein kinases. Our understanding of the biochemistry of the Hsp90 and its co-chaperones has improved greatly in the last few years, but the means by which it's essential ATPase cycle is coupled to changes in state of a client proteins remains unclear. We propose to determine the mechanism of client protein activation by Hsp90 and its co-chaperone complexes using a combinationof biochemical and structural techniques. We will focus in particular on the mechanism of Hsp90-dependent activation of protein kinases, which form the largest coherent class of Hsp90 client proteins and give Hsp90 such a key rolein the regulation and maintenance of the eukaryotic cell. Additionally, we propose to determine the functional roles of several of the co-chaperones thatregulate Hsp90 and couple it to other multi-protein cellular systems, and in particular understand how client proteins are transferred to the ubiquitin-mediated targeted protein destruction system, following pharmacological inhibition of Hsp90.
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Grant Details
Amount Awarded | 1504955 |
Applicant Surname | Pearl |
Approval Committee | Molecules, Genes and Cells Funding Committee |
Award Date | 2006-06-27T00:00:00+00:00 |
Financial Year | 2005/06 |
Grant Programme: Title | Programme Grant |
Internal ID | 080041/Z/06/Z |
Lead Applicant | Prof Laurence Pearl |
Partnership Value | 1504955 |
Planned Dates: End Date | 2010-09-30T00:00:00+00:00 |
Planned Dates: Start Date | 2006-10-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | Greater London |