6ZRQ

two-protofilament amyloid structure of S20G variant of human amylin (IAPP - islet amyloid polypeptide)

Summary for 6ZRQ

• Entry DOI: 10.2210/pdb6zrq/pdb
• Related: 6ZRF
• EMDB information: 11380 11382
• Descriptor: Islet amyloid polypeptide (1 entity in total)
• Functional Keywords: amyloid fibril type-2-diabetes early-onset, protein fibril
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 12
• Total formula weight: 46539.52

Authors

Gallardo, R.U.,Iadanza, M.G.,Ranson, N.A.,Radford, S.E. (deposition date: 2020-07-14, release date: 2020-09-30, Last modification date: 2020-11-18)

Primary citation

Gallardo, R.,Iadanza, M.G.,Xu, Y.,Heath, G.R.,Foster, R.,Radford, S.E.,Ranson, N.A.
Fibril structures of diabetes-related amylin variants reveal a basis for surface-templated assembly.
Nat.Struct.Mol.Biol., 27:1048-1056, 2020

PubMed Abstract: 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.

PubMed: 32929282
DOI: 10.1038/s41594-020-0496-3

Experimental method

ELECTRON MICROSCOPY (3.9 Å)