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Publication Abstract from PubMed

Aggregation of the peptide hormone amylin into amyloid deposits is a pathological hallmark of type-2 diabetes (T2D). While no causal link between T2D and amyloid has been established, the S20G mutation in amylin is associated with early-onset T2D. Here we report cryo-EM structures of amyloid fibrils of wild-type human amylin and its S20G variant. The wild-type fibril structure, solved to 3.6-A resolution, contains two protofilaments, each built from S-shaped subunits. S20G fibrils, by contrast, contain two major polymorphs. Their structures, solved at 3.9-A and 4.0-A resolution, respectively, share a common two-protofilament core that is distinct from the wild-type structure. Remarkably, one polymorph contains a third subunit with another, distinct, cross-beta conformation. The presence of two different backbone conformations within the same fibril may explain the increased aggregation propensity of S20G, and illustrates a potential structural basis for surface-templated fibril assembly.

Fibril structures of diabetes-related amylin variants reveal a basis for surface-templated assembly.,Gallardo R, Iadanza MG, Xu Y, Heath GR, Foster R, Radford SE, Ranson NA Nat Struct Mol Biol. 2020 Sep 14. pii: 10.1038/s41594-020-0496-3. doi:, 10.1038/s41594-020-0496-3. PMID:32929282^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.