A molecular mechanism for transthyretin amyloidogenesis

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, Michael Haertlein, Bert L. de Groot, Elisabetta Boeri Erba and V. Trevor Forsyth ()
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Ai Woon Yee: Keele University
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
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
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

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08609-z

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