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

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 h...

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Autores principales: Haupt, Melina, Blakeley, Matthew P., Fisher, Stuart J., Mason, Sax A., Cooper, Jon B., Mitchell, Edward P., Forsyth, V. Trevor
Formato: Online Artículo Texto
Lenguaje:English
Publicado: International Union of Crystallography 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224461/
https://www.ncbi.nlm.nih.gov/pubmed/25485123
http://dx.doi.org/10.1107/S2052252514021113
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author Haupt, Melina
Blakeley, Matthew P.
Fisher, Stuart J.
Mason, Sax A.
Cooper, Jon B.
Mitchell, Edward P.
Forsyth, V. Trevor
author_facet Haupt, Melina
Blakeley, Matthew P.
Fisher, Stuart J.
Mason, Sax A.
Cooper, Jon B.
Mitchell, Edward P.
Forsyth, V. Trevor
author_sort Haupt, Melina
collection PubMed
description 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.
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spelling pubmed-42244612014-12-05 Binding site asymmetry in human transthyretin: insights from a joint neutron and X-ray crystallographic analysis using perdeuterated protein Haupt, Melina Blakeley, Matthew P. Fisher, Stuart J. Mason, Sax A. Cooper, Jon B. Mitchell, Edward P. Forsyth, V. Trevor IUCrJ Research Papers 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. International Union of Crystallography 2014-10-21 /pmc/articles/PMC4224461/ /pubmed/25485123 http://dx.doi.org/10.1107/S2052252514021113 Text en © Melina Haupt et al. 2014 http://creativecommons.org/licenses/by/2.0/uk/ This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.
spellingShingle Research Papers
Haupt, Melina
Blakeley, Matthew P.
Fisher, Stuart J.
Mason, Sax A.
Cooper, Jon B.
Mitchell, Edward P.
Forsyth, V. Trevor
Binding site asymmetry in human transthyretin: insights from a joint neutron and X-ray crystallographic analysis using perdeuterated protein
title Binding site asymmetry in human transthyretin: insights from a joint neutron and X-ray crystallographic analysis using perdeuterated protein
title_full Binding site asymmetry in human transthyretin: insights from a joint neutron and X-ray crystallographic analysis using perdeuterated protein
title_fullStr Binding site asymmetry in human transthyretin: insights from a joint neutron and X-ray crystallographic analysis using perdeuterated protein
title_full_unstemmed Binding site asymmetry in human transthyretin: insights from a joint neutron and X-ray crystallographic analysis using perdeuterated protein
title_short Binding site asymmetry in human transthyretin: insights from a joint neutron and X-ray crystallographic analysis using perdeuterated protein
title_sort binding site asymmetry in human transthyretin: insights from a joint neutron and x-ray crystallographic analysis using perdeuterated protein
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224461/
https://www.ncbi.nlm.nih.gov/pubmed/25485123
http://dx.doi.org/10.1107/S2052252514021113
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