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Nat Commun. 2019 Feb 25;10(1):925. doi: 10.1038/s41467-019-08609-z.

A molecular mechanism for transthyretin amyloidogenesis.

Author information

1
Faculty of Natural Sciences, Keele University, Staffordshire, ST5 5BG, UK.
2
Institut Laue-Langevin, 71 avenue des Martyrs, 38042 Cedex 9, Grenoble, France.
3
Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077, Göttingen, Germany.
4
Heinz Maier-Leibnitz Zentrum (MLZ), Technische Universität München, 85748, Garching, Germany.
5
Univ. Grenoble Alpes, CEA, CNRS, IBS, 38000, Grenoble, France.
6
European Synchrotron Radiation Facility, 71 avenue des Martyrs, 38042 Cedex 9, Grenoble, France.
7
EMBL, Grenoble Outstation, 71 avenue des Martyrs, 38042 Cedex 9, Grenoble, France.
8
Faculty of Natural Sciences, Keele University, Staffordshire, ST5 5BG, UK. tforsyth@ill.eu.
9
Institut Laue-Langevin, 71 avenue des Martyrs, 38042 Cedex 9, Grenoble, France. tforsyth@ill.eu.

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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