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A molecular mechanism for transthyretin amyloidogenesis

Author

Listed:
  • Ai Woon Yee

    (Keele University
    Institut Laue-Langevin)

  • Matteo Aldeghi

    (Max Planck Institute for Biophysical Chemistry)

  • Matthew P. Blakeley

    (Institut Laue-Langevin)

  • Andreas Ostermann

    (Technische Universität München)

  • Philippe J. Mas

    (CEA, CNRS, IBS)

  • Martine Moulin

    (Keele University
    Institut Laue-Langevin)

  • Daniele de Sanctis

    (European Synchrotron Radiation Facility)

  • Matthew W. Bowler

    (EMBL, Grenoble Outstation)

  • Christoph Mueller-Dieckmann

    (European Synchrotron Radiation Facility)

  • Edward P. Mitchell

    (Keele University
    European Synchrotron Radiation Facility)

  • Michael Haertlein

    (Institut Laue-Langevin)

  • Bert L. de Groot

    (Max Planck Institute for Biophysical Chemistry)

  • Elisabetta Boeri Erba

    (CEA, CNRS, IBS)

  • V. Trevor Forsyth

    (Keele University
    Institut Laue-Langevin)

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.

Suggested Citation

  • Ai Woon Yee & Matteo Aldeghi & Matthew P. Blakeley & Andreas Ostermann & Philippe J. Mas & Martine Moulin & Daniele de Sanctis & Matthew W. Bowler & Christoph Mueller-Dieckmann & Edward P. Mitchell & , 2019. "A molecular mechanism for transthyretin amyloidogenesis," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08609-z
    DOI: 10.1038/s41467-019-08609-z
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    Cited by:

    1. Irina Iakovleva & Michael Hall & Melanie Oelker & Linda Sandblad & Intissar Anan & A. Elisabeth Sauer-Eriksson, 2021. "Structural basis for transthyretin amyloid formation in vitreous body of the eye," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    2. Emily G. Saccuzzo & Mubark D. Mebrat & Hailee F. Scelsi & Minjoo Kim & Minh Thu Ma & Xinya Su & Shannon E. Hill & Elisa Rheaume & Renhao Li & Matthew P. Torres & James C. Gumbart & Wade D. Van Horn & , 2024. "Competition between inside-out unfolding and pathogenic aggregation in an amyloid-forming β-propeller," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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