Molecular Mechanism of BRICHOS interacting with amyloids

已知伴侣可以影响和调节原纤维的形成。类似于小的热休克蛋白（sHSP），Bri2 BRICHOS结构域和其他BRICHOS结构域已被认为具有一般的抗淀粉样蛋白伴侣活性，具有结合不同聚集蛋白中类似基序的能力。在这个建议中，我们的目标是表征BRICHOS采用的结构机制来调节hIAPP聚集。我们将研究hIAPP以及BRICHOS，以更好地理解这种相互作用。使用溶液状态的NMR，我们将调查单体和低低聚物重量复合物的hIAPP和BRICHOS，而我们将采用MAS固态NMR来表征共聚集状态。我们将滴定BRICHOS到预形成的纤维，以及单体hIAPP，以找出BRICHOS如何影响hIAPP纤维的构象空间。已知BRICHOS会干扰二次成核。我们将表征允许重定向hIAPP聚集途径以更好地理解播种的结构机制。总的来说，该项目将深入了解细胞因子如伴侣蛋白如何能够改变原纤维结构，从而影响淀粉样蛋白对细胞的影响。

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.