Fibril structures of diabetes-related amylin variants reveal a basis for surface-templated assembly

• Published in: Nature structural & molecular biology Vol. 27; no. 11; pp. 1048 - 1056
• Main Authors: Gallardo, Rodrigo, Iadanza, Matthew G., Xu, Yong, Heath, George R., Foster, Richard, Radford, Sheena E., Ranson, Neil A.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2020; Nature Publishing Group
• Subjects: 101/28; 14/3; 631/45/470/2284; 631/535/1258/1259; Age; Agglomeration; Amylin; Amyloid - chemistry; Amyloid - genetics; Amyloid - ultrastructure; Assembly; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; Conformation; Cryoelectron Microscopy; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - pathology; Fibrils; Humans; Islet Amyloid Polypeptide - chemistry; Islet Amyloid Polypeptide - genetics; Islet Amyloid Polypeptide - ultrastructure; Life Sciences; Membrane Biology; Models, Molecular; Mutation; Point Mutation; Protein Conformation; Protein Structure; β-Amyloid
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/s41594-020-0496-3

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-Å resolution, contains two protofilaments, each built from S-shaped subunits. S20G fibrils, by contrast, contain two major polymorphs. Their structures, solved at 3.9-Å and 4.0-Å 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-β 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. Cryo-EM structures of diabetes-related amyloids formed by wild-type human amylin (IAPP) and its S20G variant reveal a mode for surface-templated fibril growth.