title: Neutron diffraction reveals sequence-specific membrane insertion of pre-fibrillar islet amyloid polypeptide and inhibition by rifampicin.
abstract: Human islet amyloid polypeptide (hIAPP) forms amyloid deposits in non-insulin-dependent diabetes mellitus (NIDDM). Pre-fibrillar hIAPP oligomers (in contrast to monomeric IAPP or mature fibrils) increase membrane permeability, suggesting an important role in the disease. In the first structural study of membrane-associated hIAPP, lamellar neutron diffraction shows that oligomeric hIAPP inserts into phospholipid bilayers, and extends across the membrane. Rifampicin, which inhibits hIAPP-induced membrane permeabilisation in functional studies, prevents membrane insertion. In contrast, rat IAPP (84% identical to hIAPP, but non-amyloidogenic) does not insert into bilayers. Our findings are consistent with the hypothesis that membrane-active pre-fibrillar hIAPP oligomers insert into beta cell membranes in NIDDM.
authors.affiliation: Veterinary Biomedical Sciences, R(D)SVS, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, UK.
authors.forename: Kia
authors.initials: K
authors.lastname: Balali-Mood
authors.forename: Richard H
authors.initials: RH
authors.lastname: Ashley
authors.forename: Thomas
authors.initials: T
authors.lastname: Hauss
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Bradshaw
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D002463:Cell Membrane Permeability; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D058228:Islet Amyloid Polypeptide; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D033363:Neutron Diffraction; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D012293:Rifampin / Q000737:chemistry / Q000494:pharmacology*; D014867:Water / Q000737:chemistry
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D008051:Lipid Bilayers; D010455:Peptides; D010743:Phospholipids; D014867:Water; D012293:Rifampin