5NFE

Neutron structure of human transthyretin (TTR) T119M mutant at room temperature to 1.85A resolution

Summary for 5NFE

• Entry DOI: 10.2210/pdb5nfe/pdb
• Descriptor: Transthyretin (2 entities in total)
• Functional Keywords: transthyretin, prealbumin, homotetramer, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 28133.56

Authors

Yee, A.W.,Moulin, M.,Blakeley, M.P.,Ostermann, A.,Cooper, J.B.,Haertlein, M.,Mitchell, E.P.,Forsyth, V.T. (deposition date: 2017-03-14, release date: 2019-01-02, Last modification date: 2024-05-01)

Primary citation

Yee, A.W.,Aldeghi, M.,Blakeley, M.P.,Ostermann, A.,Mas, P.J.,Moulin, M.,de Sanctis, D.,Bowler, M.W.,Mueller-Dieckmann, C.,Mitchell, E.P.,Haertlein, M.,de Groot, B.L.,Boeri Erba, E.,Forsyth, V.T.
A molecular mechanism for transthyretin amyloidogenesis.
Nat Commun, 10:925-925, 2019

PubMed 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.

PubMed: 30804345
DOI: 10.1038/s41467-019-08609-z

Experimental method

NEUTRON DIFFRACTION (1.85 Å)
X-RAY DIFFRACTION (1.853 Å)