Solid-State NMR Studies Reveal Native-like ß-Sheet Structures in Transthyretin Amyloid.

Structural characterization of amyloid rich in cross-ß structures is crucial for unraveling the molecular basis of protein misfolding and amyloid formation associated with a wide range of human disorders. Elucidation of the ß-sheet structure in noncrystalline amyloid has, however, remained an enormous challenge. Here we report structural analyses of the ß-sheet structure in a full-length transthyretin amyloid using solid-state NMR spectroscopy. Magic-angle-spinning (MAS) solid-state NMR was employed to investigate native-like ß-sheet structures in the amyloid state using selective labeling schemes for more efficient solid-state NMR studies. Analyses of extensive long-range (13)C-(13)C correlation MAS spectra obtained with selectively (13)CO- and (13)Cα-labeled TTR reveal that the two main ß-structures in the native state, the CBEF and DAGH ß-sheets, remain intact after amyloid formation. The tertiary structural information would be of great use for examining the quaternary structure of TTR amyloid.