Protein-protein interactions in the early stages of amyloid assembly mechanisms (360G-Wellcome-204963_Z_16_Z)
How and why proteins aggregate is an important fundamental question. It also has far-reaching biomedical importance given the increasing prevalence of amyloid-diseases in today’s ageing population. Whilst some amyloid precursors are intrinsically disordered, others are natively folded. Each must undergo major conformational changes to form amyloid fibrils. Defining these changes is key to developing therapeutic strategies. This proposal aims to achieve this by focusing on two overarching questions: What is the nature of the protein-protein interactions that initiate amyloid formation; Can we use this knowledge to develop molecules able to control aggregation in vitro and in vivo? The challenges in answering these questions lie in the heterogeneity of aggregating species, their transient/weak interactions, and the fact that amyloid precursors adopt non-native, dynamic structures. We will meet these challenges: exploiting cutting edge structural methods to map the protein-protein interactions that commit proteins to aggregate and will use the knowledge gained to inform the design of small molecules/artificial proteins able to control aggregation by targeting these surfaces. Focusing on islet-amyloid-polypeptide (involved in type II diabetes) and beta2-microglobulin (involved in systemic amyloidosis) the goal is to enhance our fundamental understanding of protein aggregation and to inspire new strategies for intervention in disease.
Where is this data from?
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Grant Details
Amount Awarded | 1836482 |
Applicant Surname | Radford |
Approval Committee | Science Interview Panel |
Award Date | 2016-11-30T00:00:00+00:00 |
Financial Year | 2016/17 |
Grant Programme: Title | Investigator Award in Science |
Internal ID | 204963/Z/16/Z |
Lead Applicant | Prof Sheena Radford |
Partnership Value | 1836482 |
Planned Dates: End Date | 2025-07-31T00:00:00+00:00 |
Planned Dates: Start Date | 2017-08-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | Yorkshire and the Humber |