title: The protofilament structure of insulin amyloid fibrils.
abstract: Under solution conditions where the native state is destabilized, the largely helical polypeptide hormone insulin readily aggregates to form amyloid fibrils with a characteristic cross-beta structure. However, there is a lack of information relating the 4.8 A beta-strand repeat to the higher order assembly of amyloid fibrils. We have used cryo-electron microscopy (EM), combining single particle analysis and helical reconstruction, to characterize these fibrils and to study the three-dimensional (3D) arrangement of their component protofilaments. Low-resolution 3D structures of fibrils containing 2, 4, and 6 protofilaments reveal a characteristic, compact shape of the insulin protofilament. Considerations of protofilament packing indicate that the cross-beta ribbon is composed of relatively flat beta-sheets rather than being the highly twisted, beta-coil structure previously suggested by analysis of globular protein folds. Comparison of the various fibril structures suggests that very small, local changes in beta-sheet twist are important in establishing the long-range coiling of the protofilaments into fibrils of diverse morphology.
authors.affiliation: Department of Crystallography, Birkbeck College, Malet Street, London WC1E 7HX, United Kingdom.
authors.forename: José L
authors.initials: JL
authors.lastname: Jiménez
authors.forename: Ewan J
authors.initials: EJ
authors.lastname: Nettleton
authors.forename: Mario
authors.initials: M
authors.lastname: Bouchard
authors.forename: Carol V
authors.initials: CV
authors.lastname: Robinson
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.forename: Helen R
authors.initials: HR
authors.lastname: Saibil
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D002417:Cattle; D020285:Cryoelectron Microscopy; D007091:Image Processing, Computer-Assisted; D066298:In Vitro Techniques; D007328:Insulin / Q000737:chemistry*; D046911:Macromolecular Substances; D008958:Models, Molecular; D017433:Protein Structure, Secondary
chemical_list: D000682:Amyloid; D007328:Insulin; D046911:Macromolecular Substances