ArticleThe Journal of biological chemistry2010
Novel Zn2+-binding sites in human transthyretin: implications for amyloidogenesis and retinol-binding protein recognition.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 47 citations in OpenAlex.
- Investigating transthyretin variants H88R and I107V in amyloid priming: From destabilization to complete dissociation.The FEBS journal · 2026Article
- Proteome and Peptidome Changes and Zn Concentration in Chicken after In Ovo Stimulation with a Multi-Strain Probiotic and Zn-Gly Chelate: Preliminary Research.Current issues in molecular biology · 2024Article
- A molecular basis for tetramer destabilization and aggregation of transthyretin Ala97Ser.Protein science : a publication of the Protein Society · 2023Article
- Linking Gas-Phase and Solution-Phase Protein Unfolding via Mobile Proton Simulations.Analytical chemistry · 2022Article
- Calcium Binds to Transthyretin with Low Affinity.Biomolecules · 2022Article
- Review
- Reenacting the Birth of a Function: Functional Divergence of HIUases and Transthyretins as Inferred by Evolutionary and Biophysical Studies.Journal of molecular evolution · 2021Article
- The interaction of zinc with the multi-functional plasma thyroid hormone distributor protein, transthyretin: evolutionary and cross-species comparative aspects.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2021Review
- THE IMS PARADOX: A PERSPECTIVE ON STRUCTURAL ION MOBILITY-MASS SPECTROMETRY.Mass spectrometry reviews · 2021Review
- Structural Analysis of the Effect of a Dual-FLAG Tag on Transthyretin.Biochemistry · 2020Article
- Native IM-Orbitrap MS: Resolving What Was Hidden.Trends in analytical chemistry : TRAC · 2020Article
- New insights into the metal-induced oxidative degradation pathways of transthyretin.Chemical communications (Cambridge, England) · 2019Article
- Zinc binding regulates amyloid-like aggregation of GAPR-1.Bioscience reports · 2019Article
- Copper mediated amyloid-β binding to Transthyretin.Scientific reports · 2018Article
- Fourier Transform-Ion Mobility-Orbitrap Mass Spectrometer: A Next-Generation Instrument for Native Mass Spectrometry.Analytical chemistry · 2018Article
- Sequential Molecular Events of Functional Trade-Offs in 5-Hydroxyisourate Hydrolase Before and After Gene Duplication Led to the Evolution of Transthyretin During Chordate Diversification.Journal of molecular evolution · 2018Article
- Controlling dissociation channels of gas-phase protein complexes using charge manipulation.Journal of the American Society for Mass Spectrometry · 2014Article
- Identification of beta-amyloid-binding sites on transthyretin.Protein engineering, design & selection : PEDS · 2012Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human transthyretin (TTR) is a homotetrameric protein involved in several amyloidoses. Zn(2+) enhances TTR aggregation in vitro, and is a component of ex vivo TTR amyloid fibrils. We report the first crystal structure of human TTR in complex with Zn(2+) at pH 4.6-7.5. All four structures reveal three tetra-coordinated Zn(2+)-binding sites (ZBS 1-3) per monomer, plus a fourth site (ZBS 4) involving amino acid residues from a symmetry-related tetramer that is not visible in solution by NMR. Zn(2+) binding perturbs loop E-α-helix-loop F, the region involved in holo-retinol-binding protein (holo-RBP) recognition, mainly at acidic pH; TTR affinity for holo-RBP decreases ∼5-fold in the presence of Zn(2+). Interestingly, this same region is disrupted in the crystal structure of the amyloidogenic intermediate of TTR formed at acidic pH in the absence of Zn(2+). HNCO and HNCA experiments performed in solution at pH 7.5 revealed that upon Zn(2+) binding, although the α-helix persists, there are perturbations in the resonances of the residues that flank this region, suggesting an increase in structural flexibility. While stability of the monomer of TTR decreases in the presence of Zn(2+), which is consistent with the tertiary structural perturbation provoked by Zn(2+) binding, tetramer stability is only marginally affected by Zn(2+). These data highlight structural and functional roles of Zn(2+) in TTR-related amyloidoses, as well as in holo-RBP recognition and vitamin A homeostasis.
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