A mechanism of potential cross-β (amyloid) fibril toxicity will have to be mediated by the (abnormal) interaction of the fibril with cellular binding partners. We are studying the fibril surface in the context of huntingtin exon-1 (HTTex1) important in Huntington’s Disease (HD). The core of HTTex1 fibrils is formed by its polyQ domain, which is expanded in HD. The Pro-rich C-terminus of HTTex1 fibrils is highly dynamic as shown by solid-state NMR and EPR. Consequently, we proposed a bottle brush model of HTTex1 fibrils in which the C-terminus forms the surface of the fibrils in the form of dynamic bristles. We show that the differences between HTTex1 fibrils of different toxicity are located in the C-terminus rather then the polyQ domain. Small fibrils with highly dynamic C-termini are more seeding competent, more accessible to protein-protein interaction, and more toxic than long, entangled fibrils.<br/>To describe the dynamics and conformational space of this C-terminus in detail, we measured site-specific R1 and R2 rates, and residual dipolar couplings via a combination of solution and solid-state NMR. We measured distance distributions throughout the C-terminus using DEER EPR. Finally, we ran MD simulations of that are in good agreement with the experimental data. With a detailed description of the HTTex1 fibril surface in hand, we are studying the interaction of HTTex1 C-terminus with the co-chaperone DNAJB1 using solid-state NMR and EPR.

Structural ensemble and dynamics of the fibril surface of huntingtin exon-1

ACS Spring Meeting 2021

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