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Title: Structural Changes Associated with Transthyretin Misfolding and Amyloid Formation Revealed by Solution and Solid-State NMR

Elucidation of structural changes involved in protein misfolding and amyloid formation is crucial for unraveling the molecular basis of amyloid formation. We report structural analyses of the amyloidogenic intermediate and amyloid aggregates of transthyretin using solution and solid-state nuclear magnetic resonance (NMR) spectroscopy. These NMR solution 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.
Authors:
 [1] ;  [1] ;  [2] ;  [2] ;  [3] ;  [4]
  1. East Carolina Univ., Greenville, NC (United States). Dept. of Chemistry
  2. Center of Interdisciplinary Magnetic Resonance (CIMAR) and National High Magnetic Field Lab. (NHMFL), Tallahassee, FL (United States)
  3. Scripps Research Inst., La Jolla, CA (United States). Dept. of Molecular and Experimental Medicine and Skaggs Inst. for Chemical Biology
  4. Univ. of California, Berkeley, CA (United States). Dept. of Chemistry
Publication Date:
Grant/Contract Number:
AC02-05CH11231; NS084138; DMR-1157490
Type:
Accepted Manuscript
Journal Name:
Biochemistry
Additional Journal Information:
Journal Volume: 55; Journal Issue: 13; Journal ID: ISSN 0006-2960
Publisher:
American Chemical Society (ACS)
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
National Institutes of Health (NIH); National Science Foundation (NSF)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
OSTI Identifier:
1379292