ArticleBiochemistry2018
NMR Measurements Reveal the Structural Basis of Transthyretin Destabilization by Pathogenic Mutations.
Article in Biochemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 47 citations in OpenAlex.
- Solution Phase Protein Dynamics: Influences of ESI Buffers on Hydration.Analytical chemistry · 2026Article
- Investigating transthyretin variants H88R and I107V in amyloid priming: From destabilization to complete dissociation.The FEBS journal · 2026Article
- Pathogenic Characterization of a Novel G47R Transthyretin Mutation in Early-Onset Amyloid Cardiomyopathy.Journal of the American Heart Association · 2026Article
- Evaluation of Cleavable Crosslinking for Characterization of Proteoform Structural Differences by Top-Down Mass Spectrometry.International journal of mass spectrometry · 2026Article
- Beyond structures: solution NMR as the quantitative engine of integrated structural biology.Frontiers in molecular biosciences · 2026Review
- Hydration (HJournal of the American Chemical Society · 2025Article
- Design and Mechanistic Analysis of a Potent Bivalent Inhibitor of Transthyretin Amyloid Fibrillogenesis.Journal of medicinal chemistry · 2025Article
- Aggregation of Transthyretin by Fluid Agitation.bioRxiv : the preprint server for biology · 2024Article
- Mispacking of the F87 sidechain drives aggregation-promoting conformational fluctuations in the subunit interfaces of the transthyretin tetramer.Protein science : a publication of the Protein Society · 2024Article
- Inhibitors of Transthyretin Amyloidosis: How to Rank Drug Candidates Using X-ray Crystallography Data.Molecules (Basel, Switzerland) · 2024Article
- Biochemical and biophysical properties of a rare TTRA81V mutation causing mild transthyretin amyloid cardiomyopathy.ESC heart failure · 2024Article
- Characterization of Transthyretin Mutation G47V Associated with Hereditary Cardiac Amyloidosis.Cardiology · 2024Article
- EGCG-Mediated Protection of Transthyretin Amyloidosis by Stabilizing Transthyretin Tetramers and Disrupting Transthyretin Aggregates.International journal of molecular sciences · 2023Article
- A molecular basis for tetramer destabilization and aggregation of transthyretin Ala97Ser.Protein science : a publication of the Protein Society · 2023Article
- Role of conformational dynamics in pathogenic protein aggregation.Current opinion in chemical biology · 2023Review
- Thyroxine metabolite-derived 3-iodothyronamine (T1AM) and synthetic analogs as efficient suppressors of transthyretin amyloidosis.Computational and structural biotechnology journal · 2023Article
- The Journey of Human Transthyretin: Synthesis, Structure Stability, and Catabolism.Biomedicines · 2022Review
- Article
- A Brief Journey through Protein Misfolding in Transthyretin Amyloidosis (ATTR Amyloidosis).International journal of molecular sciences · 2021Review
- Transthyretin Misfolding, A Fatal Structural Pathogenesis Mechanism.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Inherited mutations of transthyretin (TTR) destabilize its structure, leading to aggregation and familial amyloid disease. Although numerous crystal structures of wild-type (WT) and mutant TTRs have been determined, they have failed to yield a comprehensive structural explanation for destabilization by pathogenic mutations. To identify structural and dynamic variations that are not readily observed in the crystal structures, we used NMR to study WT TTR and three kinetically and/or thermodynamically destabilized pathogenic variants (V30M, L55P, and V122I). Sequence-corrected chemical shifts reveal important structural differences between WT and mutant TTR. The L55P mutation linked to aggressive early onset cardiomyopathy and polyneuropathy induces substantial structural perturbations in both the DAGH and CBEF β-sheets, whereas the V30M polyneuropathy-linked substitution perturbs primarily the CBEF sheet. In both variants, the structural perturbations propagate across the entire width of the β-sheets from the site of mutation. Structural changes caused by the V122I cardiomyopathy-associated mutation are restricted to the immediate vicinity of the mutation site, directly perturbing the subunit interfaces. NMR relaxation dispersion measurements show that WT TTR and the three pathogenic variants undergo millisecond time scale conformational fluctuations to populate a common excited state with an altered structure in the subunit interfaces. The excited state is most highly populated in L55P. The combined application of chemical shift analysis and relaxation dispersion to these pathogenic variants reveals differences in ground state structure and in the population of a transient excited state that potentially facilitates tetramer dissociation, providing new insights into the molecular mechanism by which mutations promote TTR amyloidosis.
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