Haupt, M and Blakeley, MP and Fisher, SJ and Mason, SA and Cooper, JB and Mitchell, EP and Forsyth, VT (2014) Binding site asymmetry in human transthyretin: insights from a joint neutron and X-ray crystallographic analysis using perdeuterated protein. IUCrJ, 1 (Pt 6). 429 - 438. ISSN 2052-2525

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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 γ-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 β-sheet and the formation of an extended cross-β structure through sequential dimer couplings. It is argued that the precursor to fibril formation is the dimeric form of the protein.

Item Type: Article
Additional Information: This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.
Uncontrolled Keywords: transthyretin; amyloid assembly; neutron crystallography; deutration
Subjects: Q Science > Q Science (General)
?? amyloid assembly ??
?? deuteration ??
?? neutron crystallography ??
?? transthyretin ??
Divisions: Faculty of Natural Sciences > School of Physical and Geographical Sciences
Related URLs:
Depositing User: Symplectic
Date Deposited: 21 Mar 2017 16:14
Last Modified: 21 Mar 2017 16:14
URI: http://eprints.keele.ac.uk/id/eprint/3045

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