Open AccessStructural Changes Associated with Transthyretin Misfolding and Amyloid Formation Revealed by Solution and Solid-State NMR
Author(s) -
Kwang Hun Lim,
Anvesh K. R. Dasari,
Ivan Hung,
Zhehong Gan,
Jeffery W. Kelly,
David E. Wemmer
Publication year - 2016
Publication title -
biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.43
H-Index - 253
eISSN - 1520-4995
pISSN - 0006-2960
DOI - 10.1021/acs.biochem.6b00164
Subject(s) - magic angle spinning , transthyretin , solid state nuclear magnetic resonance , nuclear magnetic resonance spectroscopy , chemistry , amyloid (mycology) , beta sheet , fibril , protein folding , crystallography , protein structure , biophysics , nuclear magnetic resonance , stereochemistry , biochemistry , biology , physics , inorganic chemistry , endocrinology
Elucidation of structural changes involved in protein misfolding and amyloid formation is crucial for unraveling the molecular basis of amyloid formation. Here we report structural analyses of the amyloidogenic intermediate and amyloid aggregates of transthyretin using solution and solid-state nuclear magnetic resonance (NMR) spectroscopy. Our solution NMR results show that one of the two main β-sheet structures (CBEF β-sheet) is maintained in the aggregation-competent intermediate, while the other DAGH β-sheet is more flexible on millisecond time scales. Magic-angle-spinning solid-state NMR revealed that AB loop regions interacting with strand A in the DAGH β-sheet undergo conformational changes, leading to the destabilized DAGH β-sheet.