Cargando…
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...
Autores principales: | , , , , , , |
---|---|
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 |
_version_ | 1782343354442317824 |
---|---|
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. |
format | Online Article Text |
id | pubmed-4224461 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | International Union of Crystallography |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT hauptmelina bindingsiteasymmetryinhumantransthyretininsightsfromajointneutronandxraycrystallographicanalysisusingperdeuteratedprotein AT blakeleymatthewp bindingsiteasymmetryinhumantransthyretininsightsfromajointneutronandxraycrystallographicanalysisusingperdeuteratedprotein AT fisherstuartj bindingsiteasymmetryinhumantransthyretininsightsfromajointneutronandxraycrystallographicanalysisusingperdeuteratedprotein AT masonsaxa bindingsiteasymmetryinhumantransthyretininsightsfromajointneutronandxraycrystallographicanalysisusingperdeuteratedprotein AT cooperjonb bindingsiteasymmetryinhumantransthyretininsightsfromajointneutronandxraycrystallographicanalysisusingperdeuteratedprotein AT mitchelledwardp bindingsiteasymmetryinhumantransthyretininsightsfromajointneutronandxraycrystallographicanalysisusingperdeuteratedprotein AT forsythvtrevor bindingsiteasymmetryinhumantransthyretininsightsfromajointneutronandxraycrystallographicanalysisusingperdeuteratedprotein |