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Journal Article

A molecular mechanism for transthyretin amyloidogenesis.

MPS-Authors
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Aldeghi,  M.
Research Group of Computational Biomolecular Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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de Groot,  B. L.
Research Group of Computational Biomolecular Dynamics, MPI for Biophysical Chemistry, Max Planck Society;

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3030523.pdf
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3030523_Suppl_1.pdf
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3030523_Suppl_2.pdf
(Supplementary material), 69KB

Citation

Yee, A. W., Aldeghi, M., Blakeley, M. P., Ostermann, A., Mas, P. J., Moulin, M., et al. (2019). A molecular mechanism for transthyretin amyloidogenesis. Nature Communications, 10(1): 925. doi:10.1038/s41467-019-08609-z.


Cite as: https://hdl.handle.net/21.11116/0000-0003-1672-4
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.