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

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.