Non-Linear and Flexible Regions of the Human Notch1 Extracellular Domain Revealed by High-Resolution Structural Studies
Year: 2016
Type: article
Abstract: 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.
Source: Structure
Authors: Philip C. Weisshuhn, Devon Sheppard, Paul Taylor, Pat Whiteman, Susan M. Lea, Penny A. Handford, Christina Redfield
Institution: University of Oxford
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,812
Awards: Molecular mechanisms in complement regulation and evasion., Molecular mechanisms in complement regulation and evasion., G863095010, Nuclear magnetic resonance spectroscopy as a tool to study the structure, function, dynamics and folding of proteins: University Award for a research technologist in biomolecular NMR.
OpenAlex ID: W2302883814