title: Human amylin oligomer growth and fibril elongation define two distinct phases in amyloid formation.
abstract: Human amylin (hA), a 37-amino-acid polypeptide, is one of a number of peptides with the ability to form amyloid fibrils and cause disease. It is the main constituent of the pancreatic amyloid deposits associated with type 2 diabetes. Increasing interest in early assembly intermediates rather than the mature fibrils as the cytotoxic agent has led to this study in which the smallest hA oligomers have been captured by atomic force microscopy. These are 2.3 +/- 1.9 nm in height, 23 +/- 14 nm in length, and consist of an estimated 16 hA molecules. Oligomers first grow to a height of about 6 nm before they begin to significantly elongate into fibrils. Congo red inhibits elongation but not the growth in height of hA oligomers. Two distinct phases have thus been identified in hA fibrillogenesis: lateral growth of oligomers followed by longitudinal growth into mature fibrils. These observations suggest that mature fibrils are assembled directly via longitudinal growth of full-width oligomers, making assembly by lateral association of protofibrils appear less likely.
authors.affiliation: M. E. Müller Institute for Structural Biology, Biozentrum, University of Basel, Klingelbergstrasse 70, 4056 Basel, Switzerland.
authors.forename: Janelle D
authors.initials: JD
authors.lastname: Green
authors.forename: Claire
authors.initials: C
authors.lastname: Goldsbury
authors.forename: Joerg
authors.initials: J
authors.lastname: Kistler
authors.forename: Garth J S
authors.initials: GJ
authors.lastname: Cooper
authors.forename: Ueli
authors.initials: U
authors.lastname: Aebi
mesh_terms: D000327:Adsorption; D000682:Amyloid / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D003224:Congo Red / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D058228:Islet Amyloid Polypeptide; D018625:Microscopy, Atomic Force; D010455:Peptides / Q000737:chemistry; D020005:Propanols / Q000494:pharmacology; D013997:Time Factors; D006845:Hydrocarbons, Fluorinated
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D003224:Congo Red; D058228:Islet Amyloid Polypeptide; D010455:Peptides; D020005:Propanols; C001337:hexafluoroisopropanol; D006845:Hydrocarbons, Fluorinated