Jm. Griffiths et al., ROTATIONAL RESONANCE SOLID-STATE NMR ELUCIDATES A STRUCTURAL MODEL OFPANCREATIC AMYLOID, Journal of the American Chemical Society, 117(12), 1995, pp. 3539-3546
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.