Amyloid fibril formation by various polypeptides is a biophysically interesting and biomedically important phenomenon, any understanding of which depends on molecular structural information. This presentation will cover recent results from our lab on structures of fibrils formed by amyloid-β (Aβ) peptides and by low-complexity (LC) protein sequences. This work combines solid state NMR (ssNMR) with cryogenic electron microscopy (cryoEM). Topics that may be discussed include: (i) studies of Aβ fibrils derived from brain tissue of Alzheimer's disease (AD) patients, addressing the question of whether variations in Aβ fibril structure, known as molecular-level polymorphisms, correlate with variations in characteristics of AD; (ii) the molecular structure of the predominant 40-residue Aβ polymorph from typical AD brain, which has novel conformational and symmetry features; (iii) studies of fibrils formed by the LC domain of FUS, including information about stabilizing interactions within the non-hydrophobic fibril core from ssNMR, cryoEM, and molecular dynamics simulations; (iv) speculations regarding the effect of long, disordered protein "tails" on the structure and stability of an amyloid fibril core, especially for self-similar sequences such as the LC domain of FUS..

Structure of amyloid-β and FUS low-complexity domain fibrils

ACS Spring Meeting 2021

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