ROTATIONAL RESONANCE SOLID-STATE NMR ELUCIDATES A STRUCTURAL MODEL OFPANCREATIC AMYLOID

Rotational resonance (R(2)) solid-state NMR spectroscopy was used to m easure six intercarbon distances in amyloid fibrils comprising C-13-la beled analogs of a peptide (AcHN-SNNFGAILSS-CONH2, IAPP(H)(20-29)) bas ed on residues 20-29 of the human islet amyloid polypeptide (amylin, I APP(H)). The intramolecular intercarbon distances, which constrain the peptide backbone dihedral angles (phi, psi), suggest that IAPP(H)(20- 29) adopts a highly pleated beta sheet structure in the amyloid fibril . This structure is more compact than the antiparallel beta sheet mode l formulated by Pauling to describe the silk fibril. Exaggerated pleat ing may allow intrastrand van der Waals interactions between hydrophob ic side chains. Interstrand interactions can be modeled using qualitat ive intermolecular R(2) effects which are observed in label dilution e xperiments. An intermolecular R(2) effect was observed between the C-a lpha of Ala25 and the C=O of Ile26, suggesting their proximity in the amyloid beta sheet. The R(2) SSNMR measurements allow the refinement o f our two-dimensional model of the IAPP(H)(20-29) amyloid beta sheet. The refined model may facilitate the design of molecules that bind to pancreatic amyloid. Such molecules may be useful as diagnostics or the rapeutics for type-II diabetes.