Neutron diffraction reveals sequence-specific membrane insertion of pre-fibrillar islet amyloid polypeptide and inhibition by rifampicin |
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Authors: | Balali-Mood Kia Ashley Richard H Hauss Thomas Bradshaw Jeremy P |
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Institution: | a Veterinary Biomedical Sciences, R.(D.)S.V.S., University of Edinburgh, Summerhall, Edinburgh EH9 1QH, UK b Biomedical Sciences, University of Edinburgh Medical School, George Square, Edinburgh EH8 9XD, UK c Hahn-Meitner-Institut, Glienicker Straße 100, D-14109 Berlin, Germany |
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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. |
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Keywords: | Alzheimer&rsquo s disease Diabetes mellitus Ion channel Non-insulin-dependent diabetes mellitus Phospholipid bilayer |
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