Site-specific structural order in Alzheimer's Aβ42 fibrils

Deposition of amyloid fibrils is a pathological hallmark of Alzheimer's disease. A beta 42 is the major protein whose aggregation leads to the formation of these fibrils. Understanding the detailed structure of A beta 42 fibrils is of particular importance for delineating the mechanism of A beta 42 aggregation and developing specific amyloid-targeting drugs. Here, we use site-directed spin labelling and electron paramagnetic resonance spectroscopy to study the site-specific structural order at each and every residue position in A beta 42 fibrils. Strong interactions between spin labels indicate highly ordered protein backbone at the labelling site, while weak interactions suggest disordered local structure. Our results show that A beta 42 consists of five beta-strands (residues 2-7, 10-13, 17-20, 31-36, 39-41), three turns (residues 7-8, 14-16, 37-38) and one ordered loop (residues 21-30). Spin labels introduced at beta-strand sites show strong spin-spin interactions, while spin labels at turn or loop sites show weak interactions. However, residues 24, 25 and 28 also show strong interactions between spin labels, suggesting that the loop 21-30 is partly ordered. In the context of recent structural work using solid-state N FAR and cryobM, the site-specific structural order revealed in this study provides a different perspective on backbone and side chain dynamics of A beta 42 fibrils.