Molecular conformation of a peptide fragment of transthyretin in an amyloid fibril

The molecular conformation of peptide fragment 105–115 of transthyretin, TTR(105–115), previously shown to form amyloid fibrils in vitro, has been determined by magic-angle spinning solid-state NMR spectroscopy. (13)C and (15)N linewidth measurements indicate that TTR(105–115) forms a highly ordered structure with each amino acid in a unique environment. 2D (13)C-(13)C and (15)N-(13)C-(13)C chemical shift correlation experiments, performed on three fibril samples uniformly (13)C,(15)N-labeled in consecutive stretches of 4 aa, allowed the complete sequence-specific backbone and side-chain (13)C and (15)N resonance assignments to be obtained for residues 105–114. Analysis of the (15)N, (13)CO, (13)C(α), and (13)C(β) chemical shifts allowed quantitative predictions to be made for the backbone torsion angles φ and ψ. Furthermore, four backbone (13)C–(15)N distances were determined in two selectively (13)C,(15)N-labeled fibril samples by using rotational-echo double-resonance NMR. The results show that TTR(105–115) adopts an extended β-strand conformation that is similar to that found in the native protein except for substantial differences in the vicinity of the proline residue.