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Title: Solid-State NMR Studies Reveal Native-like β-Sheet Structures in Transthyretin Amyloid

Structural characterization of amyloid rich in cross-β 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 β-sheet structure in noncrystalline amyloid has, however, remained an enormous challenge. Here we report structural analyses of the β-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 β-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 β-structures in the native state, the CBEF and DAGH β-sheets, remain intact after amyloid formation. The tertiary structural information would be of great use for examining the quaternary structure of TTR amyloid.
Authors:
 [1] ;  [1] ;  [2] ;  [2] ;  [3] ;  [3] ;  [4]
  1. East Carolina Univ., Greenville, NC (United States)
  2. National High Magnetic Field Lab. (NHMFL), Tallahassee, FL (United States)
  3. Scripps Research Inst., La Jolla, CA (United States)
  4. Univ. of California, Berkeley, CA (United States)
Publication Date:
Grant/Contract Number:
AC02-05CH11231; NS084138; DK34909; AG10770; DK46335; DMR-1157490
Type:
Accepted Manuscript
Journal Name:
Biochemistry
Additional Journal Information:
Journal Volume: 55; Journal Issue: 37; Journal ID: ISSN 0006-2960
Publisher:
American Chemical Society (ACS)
Research Org:
East Carolina Univ., Greenville, NC (United States); Scripps Research Inst., La Jolla, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE; National Inst. of Health (NIH) (United States); National Science Foundation (NSF)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
OSTI Identifier:
1377496