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

Nat Struct Mol Biol. 2020 Nov;27(11):1048-1056. doi: 10.1038/s41594-020-0496-3. Epub 2020 Sep 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / chemistry
  • Amyloid / genetics*
  • Amyloid / ultrastructure
  • Cryoelectron Microscopy
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / pathology
  • Humans
  • Islet Amyloid Polypeptide / chemistry
  • Islet Amyloid Polypeptide / genetics*
  • Islet Amyloid Polypeptide / ultrastructure
  • Models, Molecular
  • Point Mutation
  • Protein Conformation


  • Amyloid
  • Islet Amyloid Polypeptide