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Binding site asymmetry in human transthyretin: insights from a joint neutron and X-ray crystallographic analysis using perdeuterated protein.

Binding site asymmetry in human transthyretin: insights from a joint neutron and X-ray crystallographic analysis using perdeuterated protein. Thumbnail


Abstract

Human transthyretin has an intrinsic tendency to form amyloid fibrils and is heavily implicated in senile systemic amyloidosis. Here, detailed neutron structural studies of perdeuterated transthyretin are described. The analyses, which fully exploit the enhanced visibility of isotopically replaced hydrogen atoms, yield new information on the stability of the protein and the possible mechanisms of amyloid formation. Residue Ser117 may play a pivotal role in that a single water molecule is closely associated with the ?-hydrogen atoms in one of the binding pockets, and could be important in determining which of the two sites is available to the substrate. The hydrogen-bond network at the monomer-monomer interface is more extensive than that at the dimer-dimer interface. Additionally, the edge strands of the primary dimer are seen to be favourable for continuation of the ß-sheet and the formation of an extended cross-ß structure through sequential dimer couplings. It is argued that the precursor to fibril formation is the dimeric form of the protein.

Acceptance Date Sep 22, 2014
Publication Date Nov 1, 2014
Publicly Available Date Mar 28, 2024
Journal IUCrJ
Publisher International Union of Crystallography
Pages 429 - 438
DOI https://doi.org/10.1107/S2052252514021113
Keywords transthyretin; amyloid assembly; neutron crystallography; deutration
Publisher URL http://journals.iucr.org/m/issues/2014/06/00/tj5003/index.html

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