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  A molecular mechanism for transthyretin amyloidogenesis.

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.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-1672-4 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-1677-F
Genre: Journal Article

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 Creators:
Yee, A. W., Author
Aldeghi, M.1, Author              
Blakeley, M. P., Author
Ostermann, A., Author
Mas, P. J., Author
Moulin, M., Author
de Sanctis, D., Author
Bowler, M. W., Author
Mueller-Dieckmann, C., Author
Mitchell, E. P., Author
Haertlein, M., Author
de Groot, B. L.1, Author              
Boeri Erba, E., Author
Forsyth, V. T., Author
Affiliations:
1Research Group of Computational Biomolecular Dynamics, MPI for Biophysical Chemistry, Max Planck Society, ou_578573              

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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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Language(s): eng - English
 Dates: 2019-02-25
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1038/s41467-019-08609-z
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Title: Nature Communications
Source Genre: Journal
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Pages: 10 Volume / Issue: 10 (1) Sequence Number: 925 Start / End Page: - Identifier: -