skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

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

Abstract

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:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
National Institutes of Health (NIH); National Science Foundation (NSF)
OSTI Identifier:
1379292
Grant/Contract Number:  
AC02-05CH11231; NS084138; DMR-1157490
Resource 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)
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Lim, Kwang Hun, Dasari, Anvesh K. R., Hung, Ivan, Gan, Zhehong, Kelly, Jeffery W., and Wemmer, David E.. Structural Changes Associated with Transthyretin Misfolding and Amyloid Formation Revealed by Solution and Solid-State NMR. United States: N. p., 2016. Web. https://doi.org/10.1021/acs.biochem.6b00164.
Lim, Kwang Hun, Dasari, Anvesh K. R., Hung, Ivan, Gan, Zhehong, Kelly, Jeffery W., & Wemmer, David E.. Structural Changes Associated with Transthyretin Misfolding and Amyloid Formation Revealed by Solution and Solid-State NMR. United States. https://doi.org/10.1021/acs.biochem.6b00164
Lim, Kwang Hun, Dasari, Anvesh K. R., Hung, Ivan, Gan, Zhehong, Kelly, Jeffery W., and Wemmer, David E.. Mon . "Structural Changes Associated with Transthyretin Misfolding and Amyloid Formation Revealed by Solution and Solid-State NMR". United States. https://doi.org/10.1021/acs.biochem.6b00164. https://www.osti.gov/servlets/purl/1379292.
@article{osti_1379292,
title = {Structural Changes Associated with Transthyretin Misfolding and Amyloid Formation Revealed by Solution and Solid-State NMR},
author = {Lim, Kwang Hun and Dasari, Anvesh K. R. and Hung, Ivan and Gan, Zhehong and Kelly, Jeffery W. and Wemmer, David E.},
abstractNote = {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.},
doi = {10.1021/acs.biochem.6b00164},
journal = {Biochemistry},
number = 13,
volume = 55,
place = {United States},
year = {2016},
month = {3}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 16 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

The Acid-Mediated Denaturation Pathway of Transthyretin Yields a Conformational Intermediate That Can Self-Assemble into Amyloid
journal, January 1996

  • Lai, Zhihong; Colón, Wilfredo; Kelly, Jeffery W.
  • Biochemistry, Vol. 35, Issue 20
  • DOI: 10.1021/bi952501g

Transthyretin mutations in health and disease
journal, January 1995


Structure of prealbumin: Secondary, tertiary and quaternary interactions determined by Fourier refinement at 1.8 Å
journal, May 1978


Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro
journal, September 1992


Amyloid formation by globular proteins under native conditions
journal, December 2008

  • Chiti, Fabrizio; Dobson, Christopher M.
  • Nature Chemical Biology, Vol. 5, Issue 1
  • DOI: 10.1038/nchembio.131

Probing Solvent Accessibility of Transthyretin Amyloid by Solution NMR Spectroscopy
journal, November 2003

  • Olofsson, Anders; Ippel, Johannes H.; Wijmenga, Sybren S.
  • Journal of Biological Chemistry, Vol. 279, Issue 7
  • DOI: 10.1074/jbc.M310605200

Arrangement of subunits and ordering of β-strands in an amyloid sheet
journal, September 2002

  • Serag, Ahmed A.; Altenbach, Christian; Gingery, Mari
  • Nature Structural Biology, Vol. 9, Issue 10
  • DOI: 10.1038/nsb838

Experimentally Derived Structural Constraints for Amyloid Fibrils of Wild-Type Transthyretin
journal, November 2011

  • Bateman, David A.; Tycko, Robert; Wickner, Reed B.
  • Biophysical Journal, Vol. 101, Issue 10
  • DOI: 10.1016/j.bpj.2011.10.009

High-resolution molecular structure of a peptide in an amyloid fibril determined by magic angle spinning NMR spectroscopy
journal, January 2004

  • Jaroniec, C. P.; MacPhee, C. E.; Bajaj, V. S.
  • Proceedings of the National Academy of Sciences, Vol. 101, Issue 3
  • DOI: 10.1073/pnas.0304849101

An Engineered Transthyretin Monomer that Is Nonamyloidogenic, Unless It Is Partially Denatured
journal, September 2001

  • Jiang, Xin; Smith, Craig S.; Petrassi, H. Michael
  • Biochemistry, Vol. 40, Issue 38
  • DOI: 10.1021/bi011194d

Localized Structural Fluctuations Promote Amyloidogenic Conformations in Transthyretin
journal, March 2013

  • Lim, Kwang Hun; Dyson, H. Jane; Kelly, Jeffery W.
  • Journal of Molecular Biology, Vol. 425, Issue 6
  • DOI: 10.1016/j.jmb.2013.01.008

Advanced Solid-State NMR Approaches for Structure Determination of Membrane Proteins and Amyloid Fibrils
journal, May 2013

  • Tang, Ming; Comellas, Gemma; Rienstra, Chad M.
  • Accounts of Chemical Research, Vol. 46, Issue 9
  • DOI: 10.1021/ar4000168

Molecular Structure of β-Amyloid Fibrils in Alzheimer’s Disease Brain Tissue
journal, September 2013


Higher Order Amyloid Fibril Structure by MAS NMR and DNP Spectroscopy
journal, December 2013

  • Debelouchina, Galia T.; Bayro, Marvin J.; Fitzpatrick, Anthony W.
  • Journal of the American Chemical Society, Vol. 135, Issue 51
  • DOI: 10.1021/ja409050a

Amyloid Fibrils of the HET-s(218-289) Prion Form a   Solenoid with a Triangular Hydrophobic Core
journal, March 2008


Intermolecular Alignment in Y145Stop Human Prion Protein Amyloid Fibrils Probed by Solid-State NMR Spectroscopy
journal, September 2011

  • Helmus, Jonathan J.; Surewicz, Krystyna; Apostol, Marcin I.
  • Journal of the American Chemical Society, Vol. 133, Issue 35
  • DOI: 10.1021/ja206469q

Proton-Detected Solid-State NMR Spectroscopy of Fibrillar and Membrane Proteins
journal, April 2011

  • Linser, Rasmus; Dasari, Muralidhar; Hiller, Matthias
  • Angewandte Chemie International Edition, Vol. 50, Issue 19
  • DOI: 10.1002/anie.201008244

Fibrillar vs Crystalline Full-Length β-2-Microglobulin Studied by High-Resolution Solid-State NMR Spectroscopy
journal, April 2010

  • Barbet-Massin, Emeline; Ricagno, Stefano; Lewandowski, Józef R.
  • Journal of the American Chemical Society, Vol. 132, Issue 16
  • DOI: 10.1021/ja1002839

β-Sheet Core of Tau Paired Helical Filaments Revealed by Solid-State NMR
journal, August 2012

  • Daebel, Venita; Chinnathambi, Subashchandrabose; Biernat, Jacek
  • Journal of the American Chemical Society, Vol. 134, Issue 34
  • DOI: 10.1021/ja305470p

Conformational Flexibility Tunes the Propensity of Transthyretin to Form Fibrils Through Non-Native Intermediate States
journal, September 2014

  • Das, Jitendra K.; Mall, Shyam S.; Bej, Aritra
  • Angewandte Chemie International Edition, Vol. 53, Issue 47
  • DOI: 10.1002/anie.201407323

Observation of spin exchange by two-dimensional fourier transform 13C cross polarization-magic-angle spinning
journal, May 1982

  • Szeverenyi, Nikolaus M.; Sullivan, Mark J.; Maciel, Gary E.
  • Journal of Magnetic Resonance (1969), Vol. 47, Issue 3
  • DOI: 10.1016/0022-2364(82)90213-X

Rotational resonance in solid state NMR
journal, April 1988


Conformational Flexibility of Y145Stop Human Prion Protein Amyloid Fibrils Probed by Solid-State Nuclear Magnetic Resonance Spectroscopy
journal, February 2010

  • Helmus, Jonathan J.; Surewicz, Krystyna; Surewicz, Witold K.
  • Journal of the American Chemical Society, Vol. 132, Issue 7
  • DOI: 10.1021/ja909827v

Considerably Unfolded Transthyretin Monomers Preceed and Exchange with Dynamically Structured Amyloid Protofibrils
journal, June 2015

  • Groenning, Minna; Campos, Raul I.; Hirschberg, Daniel
  • Scientific Reports, Vol. 5, Issue 1
  • DOI: 10.1038/srep11443

    Works referencing / citing this record:

    Probing conformational changes of monomeric transthyretin with second derivative fluorescence
    journal, July 2019

    • Jazaj, Denisa; Ghadami, Seyyed Abolghasem; Bemporad, Francesco
    • Scientific Reports, Vol. 9, Issue 1
    • DOI: 10.1038/s41598-019-47230-4

    Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers
    journal, January 2019


    Kinetic and structural comparison of a protein’s cotranslational folding and refolding pathways
    journal, May 2018

    • Samelson, Avi J.; Bolin, Eric; Costello, Shawn M.
    • Science Advances, Vol. 4, Issue 5
    • DOI: 10.1126/sciadv.aas9098

    Biophysical characterization and modulation of Transthyretin Ala97Ser
    journal, September 2019

    • Liu, Yo‐Tsen; Yen, Yueh‐Jung; Ricardo, Frans
    • Annals of Clinical and Translational Neurology, Vol. 6, Issue 10
    • DOI: 10.1002/acn3.50887