beta2-microglobulin amyloid: Native-like assembly or conformational conversion? (360G-Wellcome-080859_B_06_Z)

£222,110

How proteins aggregate into amyloid fibrils is a key question in structural biology. Although the amino acid sequence dictates the structure of native proteins, it is now clearthat polypeptide chains can adopt an alternative conformation based upon the cross-beta structure of amyloid. Despite enormous interest in this field, the structure of amyloid fibrils, particularly those from biomedically-relevant proteins, remains unknown. Here we propose to determine the 3D structure and subunit arrangement of amyloid fibrils formed from the 99-residue protein,beta-2- microglobulin (â2m), combining cryo-electron microscopy (Saibil, Birkbeck) andprotein chemical analysis (Radford, Leeds). Building on remarkable 3D density maps recently obtained of â2m fibrils formed in vitro, we propose to determine structural restraints using cross-linking and fluorescence experiments to enable model building, and to further test and refine these models using mutagenesis. In parallel, we will improve the cryo-EM maps by collectinglarger data sets, allowing finer subdivision of the image data into more uniform subsets, and will use site-specific nanogold labelling to guide docking of the chain into the electron density maps. The overall aim is to answer the fundamental question of how the same polypeptide chain can fold into two structures: a functional monomer and an aggregated polymer.

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Grant Details

Amount Awarded 222110
Applicant Surname Radford
Approval Committee Molecules, Genes and Cells Funding Committee
Award Date 2006-11-01T00:00:00+00:00
Financial Year 2006/07
Grant Programme: Title Project Grant
Internal ID 080859/B/06/Z
Lead Applicant Prof Sheena Radford
Other Applicant(s) Prof Helen Saibil
Partnership Value 222110
Planned Dates: End Date 2010-08-31T00:00:00+00:00
Planned Dates: Start Date 2007-09-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Yorkshire and the Humber