A molecular mechanism for transthyretin amyloidogenesis

Yee, Ai Woon; Aldeghi, Matteo; Blakeley, Matthew P.; Ostermann, Andreas; Mas, Philippe J.; Moulin, Martine; de Sanctis, Daniele; Bowler, Matthew W.; Mueller-Dieckmann, Christoph; Mitchell, Edward P.; Haertlein, Michael; de Groot, Bert L.; Boeri Erba, Elisabetta; Forsyth, V. Trevor

doi:10.1038/s41467-019-08609-z

Cited by 139Amyloidosis: Diagnosis, Treatment, OutcomesPrion Diseases and Protein MisfoldingAlzheimer's disease research and treatments

A molecular mechanism for transthyretin amyloidogenesis

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Yee, Ai Woon, Aldeghi, Matteo, Blakeley, Matthew P., Ostermann, Andreas, Mas, Philippe J., Moulin, Martine, de Sanctis, Daniele, Bowler, Matthew W. +6 more·2019·Nature Communications

DOI 10.1038/s41467-019-08609-zPMC PMC6390107

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Abstract

Human transthyretin (TTR) is implicated in several fatal forms of amyloidosis. Many mutations of TTR have been identified; most of these are pathogenic, but some offer protective effects. The molecular basis underlying the vastly different fibrillation behaviours of these TTR mutants is poorly understood. Here, on the basis of neutron crystallography, native mass spectrometry and modelling studies, we propose a mechanism whereby TTR can form amyloid fibrils via a parallel equilibrium of partially unfolded species that proceeds in favour of the amyloidogenic forms of TTR. It is suggested that unfolding events within the TTR monomer originate at the C-D loop of the protein, and that destabilising mutations in this region enhance the rate of TTR fibrillation. Furthermore, it is proposed that the binding of small molecule drugs to TTR stabilises non-amyloidogenic states of TTR in a manner similar to that occurring for the protective mutants of the protein.

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In relatively simple cases, native MS mass alone can suffice to indicate the number of monomers in a complex and determine differences in complex makeup.
“In relatively simple cases, this can suffice to indicate the number of monomers in a complex and determine differences in complex makeup.”
From Higher-order structural characterisation of native proteins and complexes by top-down mass spectrometry (2020) · cites this paper as [21]

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Haupt, M., Blakeley, M. P., Teixeira, S. C. M., et al. (2011) · Acta Crystallographica Section F Structural Biology and Crystallization Communications · doi:10.1107/s1744309111036244 · Cited by 5 · see citing works
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Higher-order structural characterisation of native proteins and complexes by top-down mass spectrometry
Zhou, M., Lantz, C., Brown, K. A., Ge, Y., Paša-Tolić, L., Loo, J. A., & Lermyte, F. (2020) · Chemical Science · doi:10.1039/d0sc04392c · Cited by 146 · see citing works

Authors: Yee, A. W., Aldeghi, M., Blakeley, M. P., Ostermann, A., Mas, P. J., Moulin, M., de Sanctis, D., Bowler, M. W., Mueller-Dieckmann, C., Mitchell, E. P., Haertlein, M., de Groot, B. L., Boeri Erba, E., & Forsyth, V. T.
Affiliations: Institut Laue-Langevin (FR)
Max Planck Institute for Biophysical Chemistry (DE)
Heinz Maier-Leibnitz Zentrum (DE)
Centre National de la Recherche Scientifique (FR)
European Molecular Biology Laboratory (FR)
European Synchrotron Radiation Facility (FR)
Corresponding author: Forsyth, V. Trevor
ORCID: Yee, Ai Woon
Aldeghi, Matteo
Blakeley, Matthew P.
Ostermann, Andreas
Mas, Philippe J.
Moulin, Martine
Bowler, Matthew W.
Mitchell, Edward P.
Haertlein, Michael
Forsyth, V. Trevor
Venue: Nature Communications
Publisher: Springer Science and Business Media LLC
Published: 2019-02-25
Volume: 10
Issue: 1
Pages: 925-925
ISSN: 2041-1723 (ISSN-L)
DOI: 10.1038/s41467-019-08609-z
PMC: PMC6390107
OpenAlex: W2915131983
Cited by: 139
References: 84
Citations by year: 2026: 11 · 2025: 12 · 2024: 27 · 2023: 23 · 2022: 18 · 2021: 20 · 2020: 21 · 2019: 7
FWCI: 5.46
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
Locations: Nature Communications (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, other-oa)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Keele Research Repository (Keele University) (submittedVersion, cc-by)
MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
HAL (submittedVersion, cc-by)
RePEc: Research Papers in Economics (submittedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
iMPULSE (Heinz Maier-Leibnitz Zentrum) (submittedVersion)
mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion, other-oa)
GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
Funders: Alexander von Humboldt-Stiftung
Agence Nationale de la Recherche (ANR- 10-INSB-05, ANR-10-INSB-05-02, 10-INSB-05-02, ANR-10, ANR-10-LABX, ANR-10-LABX-49-01, ANR-10-INBS-0005, ANR-10-LABX-0049)
Centre National de la Recherche Scientifique (ANR-10-LABX-49-01)
Keele University
French Infrastructure for Integrated Structural Biology (ANR-10-INSB- 05–02, UMS 3518, ANR-10- INSB-05, INSB-05, ANR-10-LABX-49-01)
Engineering and Physical Sciences Research Council (GR/R99393/01, EP/C015452/1)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Amyloidosis: Diagnosis, Treatment, Outcomes
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords: prealbumin, amyloidogenesis, amyloid fibril formation, TTR mutations, protein unfolding, partially unfolded state, amyloidosis, protein stability
MeSH terms: Amyloidosis, Humans, Kinetics, Models, Molecular, Mutation, Prealbumin, Protein Conformation, Protein Folding, Protein Unfolding

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A molecular mechanism for transthyretin amyloidogenesis

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