Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2001 Mar 2;306(4):733-44.
doi: 10.1006/jmbi.2000.4415.

Transthyretin stability as a key factor in amyloidogenesis: X-ray analysis at atomic resolution

M P Sebastião  1 , V Lamzin, M J Saraiva, A M Damas
Affiliations

Transthyretin stability as a key factor in amyloidogenesis: X-ray analysis at atomic resolution

M P Sebastião et al. J Mol Biol. .

Abstract

Transthyretin (TTR) amyloidosis is a conformational disturbance, which, like other amyloidoses, represents a life threat. Here, we report a TTR variant, TTR Thr119Met, that has been shown to have a protective role in the development of clinical symptoms in carriers of TTR Val30Met, one of the most frequent variants among TTR amyloidosis patients. In order to understand this effect, we have determined the structures of the TTR Val30Met/Thr119Met double mutant isolated from the serum of one patient and of both the native and thyroxine complex of TTR Thr119Met. Major conclusions are: (i) new H-bonds within each monomer and monomer-monomer inter-subunit contacts, e.g. Ser117-Ser117 and Met119-Tyr114, increase protein stability, possibly leading to the protective effect of the TTR Val30Met/Thr119Met variant when compared to the single variant TTR Val30Met. (ii) The mutated residue (Met119) extends across the thyroxine binding channel inducing conformational changes that lead to closer contacts between different dimers within the tetramer. The data, at atomic resolution, were essential to detect, for the first time, the subtle changes in the inter-subunit contacts of TTR, and explain the non-amyloidogenic potential of the TTR Thr119Met variant, improving considerably current research on the TTR amyloid fibril formation pathway.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

  • Whole-genome sequence-based analysis of thyroid function.
    Taylor PN, Porcu E, Chew S, Campbell PJ, Traglia M, Brown SJ, Mullin BH, Shihab HA, Min J, Walter K, Memari Y, Huang J, Barnes MR, Beilby JP, Charoen P, Danecek P, Dudbridge F, Forgetta V, Greenwood C, Grundberg E, Johnson AD, Hui J, Lim EM, McCarthy S, Muddyman D, Panicker V, Perry JR, Bell JT, Yuan W, Relton C, Gaunt T, Schlessinger D, Abecasis G, Cucca F, Surdulescu GL, Woltersdorf W, Zeggini E, Zheng HF, Toniolo D, Dayan CM, Naitza S, Walsh JP, Spector T, Davey Smith G, Durbin R, Richards JB, Sanna S, Soranzo N, Timpson NJ, Wilson SG; UK0K Consortium. Taylor PN, et al. Nat Commun. 2015 Mar 6;6:5681. doi: 10.1038/ncomms6681. Nat Commun. 2015. PMID: 25743335 Free PMC article.
  • Development of a Highly Potent Transthyretin Amyloidogenesis Inhibitor: Design, Synthesis, and Evaluation.
    Pinheiro F, Pallarès I, Peccati F, Sánchez-Morales A, Varejão N, Bezerra F, Ortega-Alarcon D, Gonzalez D, Osorio M, Navarro S, Velázquez-Campoy A, Almeida MR, Reverter D, Busqué F, Alibés R, Sodupe M, Ventura S. Pinheiro F, et al. J Med Chem. 2022 Nov 10;65(21):14673-14691. doi: 10.1021/acs.jmedchem.2c01195. Epub 2022 Oct 28. J Med Chem. 2022. PMID: 36306808 Free PMC article.
  • A molecular mechanism for transthyretin amyloidogenesis.
    Yee AW, Aldeghi M, Blakeley MP, Ostermann A, Mas PJ, Moulin M, de Sanctis D, Bowler MW, Mueller-Dieckmann C, Mitchell EP, Haertlein M, de Groot BL, Boeri Erba E, Forsyth VT. Yee AW, et al. Nat Commun. 2019 Feb 25;10(1):925. doi: 10.1038/s41467-019-08609-z. Nat Commun. 2019. PMID: 30804345 Free PMC article.
  • Sequence-dependent denaturation energetics: A major determinant in amyloid disease diversity.
    Hammarström P, Jiang X, Hurshman AR, Powers ET, Kelly JW. Hammarström P, et al. Proc Natl Acad Sci U S A. 2002 Dec 10;99 Suppl 4(Suppl 4):16427-32. doi: 10.1073/pnas.202495199. Epub 2002 Sep 25. Proc Natl Acad Sci U S A. 2002. PMID: 12351683 Free PMC article.
  • Cholesterol and Sphingomyelin Uniquely Alter the Rate of Transthyretin Aggregation and Decrease the Toxicity of Amyloid Fibrils.
    Ali A, Zhaliazka K, Dou T, Holman AP, Kurouski D. Ali A, et al. J Phys Chem Lett. 2023 Dec 14;14(49):10886-10893. doi: 10.1021/acs.jpclett.3c02613. Epub 2023 Nov 30. J Phys Chem Lett. 2023. PMID: 38033106 Free PMC article.
See all "Cited by" articles

Publication types

LinkOut - more resources