Multidisciplinary studies of the folding of structurally related proteins: how sequence variation affects protein folding, stability, mechanics and disease. (360G-Wellcome-064417_Z_01_A)

£1,319,905

The central theme of this proposal is to investigate the relationship between protein sequence, folding, function and disease at the molecular level. We use a powerful multidisciplinary approach combining biophysical, protein engineering, structural, computational and bioinformatics techniques. Four closely related areas of research are described:Core Studies: The Folding of Related Proteins. How far can we explain (or predict) differences within and between families? We will investigate the relative importance of sequence, secondary structure, topology and chain connectivity.Studies of Multidomain ProteinsOver 75% of human proteins have more than one domain. We will investigate how the folding of one domain is affected by its neighbours and how misfolding is avoided.Mutations and Disease.Most pathogenic mutations are thought to affect protein stability. We will investigate pathogenic mutationsin all-a proteins to see how far it is possible to predict these effects from model proteins. We will compare pathogenic mutations and SNPs on a quantitative basis.Molecular Basis of Protein ElasticityIf a protein is to remain active in the presence of an external force it has to remain folded. How this is achieved will be investigated by combining atomic force microscopy, protein engineering and simulation.

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Grant Details

Amount Awarded 1319905
Applicant Surname Clarke
Approval Committee Basic Science Interview Committee
Award Date 2006-06-01T00:00:00+00:00
Financial Year 2005/06
Grant Programme: Title Senior Research Fellowship Basic Renewal
Internal ID 064417/Z/01/A
Lead Applicant Prof Jane Clarke
Partnership Value 1319905
Planned Dates: End Date 2011-09-30T00:00:00+00:00
Planned Dates: Start Date 2006-10-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region East of England
Sponsor(s) Prof Jeremy Sanders, Prof Sir Alan Fersht