Many amyloid precursors are intrinsically disordered initially, yet fold to highly organised cross-b structures during amyloid formation. How this conformational transition occurs structurally is not clear, with the initiating steps in aggregation being difficult to study because of the dynamics and heterogeneity of the species involved. It is also clear that the energy landscape for aggregation into amyloid results in potentially many different amyloid folds. In this seminar I will discuss these concepts, drawing on recent results from our laboratory on the amyloidogenic proteins α-synuclein (αSyn) and islet associated polypeptide (IAPP). I will show how, by combining kinetic analysis of aggregation combined with structural analysis of intermediates and fibrils, we are beginning to link the pathway of structural conversion from the initial unfolded monomer to the cross-beta amyloid fold. Our overarching aim is to better understand the mechanisms of amyloid assembly so as to find the weak point(s), for therapeutic intervention.
Published on June 13, 2023