Neutron diffraction reveals sequence-specific membrane insertion of pre-fibrillar islet amyloid polypeptide and inhibition by rifampicin

K Balali-Mood, R H Ashley, T Hauss, Jeremy Bradshaw

Research output: Contribution to journalArticlepeer-review

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 MAPP, 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 MAPP oligomers insert into beta cell membranes in NIDDM. (C) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)1143-1148
Number of pages6
JournalFEBS Letters
Volume579
Issue number5
DOIs
Publication statusPublished - 14 Feb 2005

Keywords

  • Alzheimer's disease
  • diabetes mellitus
  • ion channel
  • non-insulin-dependent diabetes mellitus
  • phospholipid bilayer
  • SALMON-CALCITONIN
  • PROTEINS
  • CONFORMATIONS
  • LIPOSOMES
  • MECHANISM
  • TOXICITY
  • CHANNEL

Cite this