Insights into the amyloid folding problem from solid-state NMR.

Amyloid fibrils are filamentous aggregates, with typical diameters of 10 nm and lengths on the order of microns, formed by a large class of peptides and proteins with disparate sequences and with molecular masses ranging from less than 1 kDa to tens of kilodaltons. Figure 1 shows typical amyloid fibrils as they appear in electron microscopy (EM)1 measurements. Current interest in amyloid fibrils in the biomedical community stems from the fact that amyloid fibrils deposit in the affected organs of the so-called amyloid diseases (1). Several amyloid diseases, including Alzheimer’s disease, type 2 diabetes, transmissible spongiform encephalopathies, and Parkinson’s disease, constitute major public health problems. The precise role of amyloid deposits in these diseases has not been settled, but amyloid deposition is likely to be at least a contributing factor to their etiology (2, 3). In the biophysical and biochemical communities, interest in amyloid fibrils additionally stems from the observation that the amyloid fibril appears to be a stable structural state of a generic polypeptide chain (4, 5) and from the lack of a comprehensive explanation for this observation. At the level of EM images, amyloid fibrils formed by peptides and proteins with unrelated sequences appear at least similar, if not identical. Thus, amyloid fibrillization poses a problem that is opposite to the familiar protein folding problem. Whereas in the protein folding problem one seeks to understand how the diverse three-dimensional structures of proteins are determined uniquely by their amino acid sequences, in the amyloid folding problem one seeks to understand how a single structure can be common to a great many unrelated sequences.