Emerging Structural Understanding of Amyloid Fibrils by Solid-State NMR

Amyloid structures at atomic resolution have remained elusive mainly because of their extensive polymorphism and because their polymeric properties have hampered structural studies by classical approaches. Progress in sample preparation, as well as solid-state NMR methods, recently enabled the determination of high-resolution 3D structures of fibrils such as the amyloid-β fibril, which is involved in Alzheimer’s disease. Notably, the simultaneous but independent structure determination of Aβ1-42, a peptide that forms fibrillar deposits in the brain of Alzheimer patients, by two independent laboratories, which yielded virtually identical results, has highlighted how structures can be obtained that allow further functional investigation. Complete atomic-resolution structures of disease-related amyloid fibril have become available, in particular for amyloid β. They are based on solid-state NMR restraints combined with electron-microscopic mass-per-length data. There is mounting evidence that functional amyloids play an important role in biology and medicine. Amyloids show a higher structural complexity than previously assumed and this opens an avenue for rational drug design. Drugs need to be selective to avoid interfering with functional proteins in amyloid form. Polymorphism is an important feature of many amyloids which can now be explored in more detail. The structural homogeneity of a sample can now be established before biophysical experiments are performed.