Molecular Mechanism of BRICHOS interacting with amyloids

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Chaperones are known to affect and modulate fibril formation. In analogy to small heat shock proteins (sHSPs), the Bri2 BRICHOS domain and other BRICHOS domains have been suggested to possess a general anti-amyloid chaperone activity with the ability to bind similar motifs in different aggregating proteins. In this proposal, we aim to characterize the structural mechanisms that BRICHOS employs to modulate hIAPP aggregation. We will study both hIAPP as well as BRICHOS to better understand this interaction. Using solution-state NMR, we will investigate monomeric and low oligomeric weight complexes of hIAPP and BRICHOS, while we will employ MAS solid-state NMR to characterize the co-aggregated state. We will titrate BRICHOS to preformed fibrils, as well as to monomeric hIAPP to find out how BRICHOS impacts the conformational space of hIAPP fibrils. BRICHOS is known to interfere with secondary nucleation. We will characterize the structural mechanism that allows to redirect the hIAPP aggregation pathway to yield a better understanding of seeding. Overall, the project will yield insight into the question how cellular factors such as chaperones are able to modify fibril structure which in turn impacts the effect of amyloids on cells.