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

Lim, Kwang Hun; Dasari, Anvesh K.  R.; Hung, Ivan; Gan, Zhehong; Kelly, Jeffery W.; Wemmer, David E.

doi:10.1021/acs.biochem.6b00164

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

Journal Article · Mon Mar 21 00:00:00 EDT 2016 · Biochemistry

DOI:https://doi.org/10.1021/acs.biochem.6b00164· OSTI ID:1379292

Lim, Kwang Hun ^[1]; Dasari, Anvesh K. R. ^[1]; Hung, Ivan ^[2]; Gan, Zhehong ^[2]; Kelly, Jeffery W. ^[3]; Wemmer, David E. ^[4]

East Carolina Univ., Greenville, NC (United States). Dept. of Chemistry
Center of Interdisciplinary Magnetic Resonance (CIMAR) and National High Magnetic Field Lab. (NHMFL), Tallahassee, FL (United States)
Scripps Research Inst., La Jolla, CA (United States). Dept. of Molecular and Experimental Medicine and Skaggs Inst. for Chemical Biology
Univ. of California, Berkeley, CA (United States). Dept. of Chemistry

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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: AC02-05CH11231; NS084138; DMR-1157490

OSTI ID:: 1379292

Journal Information:: Biochemistry, Vol. 55, Issue 13; ISSN 0006-2960

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 35 works

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Probing conformational changes of monomeric transthyretin with second derivative fluorescence Jazaj, Denisa; Ghadami, Seyyed Abolghasem; Bemporad, Francesco Scientific Reports, Vol. 9, Issue 1 https://doi.org/10.1038/s41598-019-47230-4	journal	July 2019
Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers Dasari, Anvesh K. R.; Hughes, Robert M.; Wi, Sungsool Scientific Reports, Vol. 9, Issue 1 https://doi.org/10.1038/s41598-018-37230-1	journal	January 2019
Exploration of the Misfolding Mechanism of Transthyretin Monomer: Insights from Hybrid-Resolution Simulations and Markov State Model Analysis Zhou, Shuangyan; Cheng, Jie; Yang, Ting Biomolecules, Vol. 9, Issue 12 https://doi.org/10.3390/biom9120889	journal	December 2019
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Clinical Presentation, Diagnosis and Treatment of TTR Amyloidosis Kapoor, Mahima; Rossor, Alexander M.; Laura, Matilde Journal of Neuromuscular Diseases, Vol. 6, Issue 2 https://doi.org/10.3233/jnd-180371	journal	May 2019

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