Protein quality control: Chaperone-substrate interactions and cellular aggregates. (360G-Wellcome-089050_Z_09_Z)

£1,062,536

This project is concerned with molecular and cellular aspects of protein quality control. We will carry out structural analyses of molecular chaperones at different stages of protein folding or disaggregation by cryo electron microscopy and single particle analysis. To understand the mechanism of assisted folding and the structural basis for substrate selectivity in bacterial and archaeal chaperonins, proteins trapped or folding inside chaperonin complexes will be imaged. We will also investigat e complexes of the yeast chaperone Hsp104 with model and physiological substrate proteins. Hsp104 is one of a unique group of chaperones capable of dissolving aggregates, and is essential for the propagation of yeast prions. A new approach initiated by the PI s sabbatical is cryo electron tomography of vitrified cell sections to study the three-dimensional structure of yeast prions in situ. In parallel, biochemically isolated prion aggregates will be examined by tomography, along with prion fi brils reconstituted with the Hsp100 and the Hsp70 system chaperones involved in their propagation. We will then apply these methods to neuroblastoma cells stably infected with mouse prions, the causative agent of transmissible encephalopathies. The approaches developed should eventually be applicable to vitrified sections of brain tissue of animal models of neurodegenerative disease.

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Grant Details

Amount Awarded 1062536
Applicant Surname Saibil
Approval Committee Molecules, Genes and Cells Funding Committee
Award Date 2009-06-26T00:00:00+00:00
Financial Year 2008/09
Grant Programme: Title Programme Grant
Internal ID 089050/Z/09/Z
Lead Applicant Prof Helen Saibil
Partnership Value 1062536
Planned Dates: End Date 2015-12-31T00:00:00+00:00
Planned Dates: Start Date 2010-04-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Greater London