Cargando…

Non-Linear and Flexible Regions of the Human Notch1 Extracellular Domain Revealed by High-Resolution Structural Studies

The Notch receptor is a key component of a core metazoan signaling pathway activated by Delta/Serrate/Lag-2 ligands expressed on an adjacent cell. This results in a short-range signal with profound effects on cell-fate determination, cell proliferation, and cell death. Key to understanding receptor...

Descripción completa

Detalles Bibliográficos
Autores principales: Weisshuhn, Philip C., Sheppard, Devon, Taylor, Paul, Whiteman, Pat, Lea, Susan M., Handford, Penny A., Redfield, Christina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826273/
https://www.ncbi.nlm.nih.gov/pubmed/26996961
http://dx.doi.org/10.1016/j.str.2016.02.010
_version_ 1782426321223155712
author Weisshuhn, Philip C.
Sheppard, Devon
Taylor, Paul
Whiteman, Pat
Lea, Susan M.
Handford, Penny A.
Redfield, Christina
author_facet Weisshuhn, Philip C.
Sheppard, Devon
Taylor, Paul
Whiteman, Pat
Lea, Susan M.
Handford, Penny A.
Redfield, Christina
author_sort Weisshuhn, Philip C.
collection PubMed
description The Notch receptor is a key component of a core metazoan signaling pathway activated by Delta/Serrate/Lag-2 ligands expressed on an adjacent cell. This results in a short-range signal with profound effects on cell-fate determination, cell proliferation, and cell death. Key to understanding receptor function is structural knowledge of the large extracellular portion of Notch which contains multiple repeats of epidermal growth factor (EGF)-like domains. Here we investigate the EGF4-13 region of human Notch1 (hN1) using a multidisciplinary approach. Ca(2+)-binding measurements, X-ray crystallography, {(1)H}-(15)N heteronuclear nuclear Overhauser effects, and residual dipolar couplings support a non-linear organization for the EGF4-13 region with a rigid, bent conformation for EGF4-7 and a single flexible linkage between EGF9 and EGF10. These data allow us to construct an informed model for EGF10-13 which, in conjunction with comparative binding studies, demonstrates that EGF10 has an important role in determining Notch receptor sensitivity to Dll-4.
format Online
Article
Text
id pubmed-4826273
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Cell Press
record_format MEDLINE/PubMed
spelling pubmed-48262732016-04-19 Non-Linear and Flexible Regions of the Human Notch1 Extracellular Domain Revealed by High-Resolution Structural Studies Weisshuhn, Philip C. Sheppard, Devon Taylor, Paul Whiteman, Pat Lea, Susan M. Handford, Penny A. Redfield, Christina Structure Article The Notch receptor is a key component of a core metazoan signaling pathway activated by Delta/Serrate/Lag-2 ligands expressed on an adjacent cell. This results in a short-range signal with profound effects on cell-fate determination, cell proliferation, and cell death. Key to understanding receptor function is structural knowledge of the large extracellular portion of Notch which contains multiple repeats of epidermal growth factor (EGF)-like domains. Here we investigate the EGF4-13 region of human Notch1 (hN1) using a multidisciplinary approach. Ca(2+)-binding measurements, X-ray crystallography, {(1)H}-(15)N heteronuclear nuclear Overhauser effects, and residual dipolar couplings support a non-linear organization for the EGF4-13 region with a rigid, bent conformation for EGF4-7 and a single flexible linkage between EGF9 and EGF10. These data allow us to construct an informed model for EGF10-13 which, in conjunction with comparative binding studies, demonstrates that EGF10 has an important role in determining Notch receptor sensitivity to Dll-4. Cell Press 2016-04-05 /pmc/articles/PMC4826273/ /pubmed/26996961 http://dx.doi.org/10.1016/j.str.2016.02.010 Text en © 2016 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Weisshuhn, Philip C.
Sheppard, Devon
Taylor, Paul
Whiteman, Pat
Lea, Susan M.
Handford, Penny A.
Redfield, Christina
Non-Linear and Flexible Regions of the Human Notch1 Extracellular Domain Revealed by High-Resolution Structural Studies
title Non-Linear and Flexible Regions of the Human Notch1 Extracellular Domain Revealed by High-Resolution Structural Studies
title_full Non-Linear and Flexible Regions of the Human Notch1 Extracellular Domain Revealed by High-Resolution Structural Studies
title_fullStr Non-Linear and Flexible Regions of the Human Notch1 Extracellular Domain Revealed by High-Resolution Structural Studies
title_full_unstemmed Non-Linear and Flexible Regions of the Human Notch1 Extracellular Domain Revealed by High-Resolution Structural Studies
title_short Non-Linear and Flexible Regions of the Human Notch1 Extracellular Domain Revealed by High-Resolution Structural Studies
title_sort non-linear and flexible regions of the human notch1 extracellular domain revealed by high-resolution structural studies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826273/
https://www.ncbi.nlm.nih.gov/pubmed/26996961
http://dx.doi.org/10.1016/j.str.2016.02.010
work_keys_str_mv AT weisshuhnphilipc nonlinearandflexibleregionsofthehumannotch1extracellulardomainrevealedbyhighresolutionstructuralstudies
AT shepparddevon nonlinearandflexibleregionsofthehumannotch1extracellulardomainrevealedbyhighresolutionstructuralstudies
AT taylorpaul nonlinearandflexibleregionsofthehumannotch1extracellulardomainrevealedbyhighresolutionstructuralstudies
AT whitemanpat nonlinearandflexibleregionsofthehumannotch1extracellulardomainrevealedbyhighresolutionstructuralstudies
AT leasusanm nonlinearandflexibleregionsofthehumannotch1extracellulardomainrevealedbyhighresolutionstructuralstudies
AT handfordpennya nonlinearandflexibleregionsofthehumannotch1extracellulardomainrevealedbyhighresolutionstructuralstudies
AT redfieldchristina nonlinearandflexibleregionsofthehumannotch1extracellulardomainrevealedbyhighresolutionstructuralstudies