A molecular mechanism for transthyretin amyloidogenesis

Nature Communications
Ai Woon YeeV Trevor Forsyth

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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Methods Mentioned

BETA
four hybrid
X-ray
neutron crystallography
NMR
gel filtration
gel
neutron diffraction
neutron scattering

Software Mentioned

gci
PyMC3
CCP4
ReadySet
mdtraj
ProtoMS
FMA
Coot
LAUE
BIODIFF

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