Notch–Jagged signaling complex defined by an interaction mosaic

The Notch signaling system links cellular fate to that of its neighbors, driving proliferation, apoptosis, and cell differentiation in metazoans, whereas dysfunction leads to debilitating developmental disorders and cancers. Other than a five-by-five domain complex, it is unclear howthe 40 extracell...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 30; pp. 1 - 12
Main Authors:	Zeronian, Matthieu R., Klykov, Oleg, de Montserrat, Júlia Portell i, Konijnenberg, Maria J., Gaur, Anamika, Scheltema, Richard A., Janssen, Bert J. C.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 27-07-2021
Subjects:	Animals Apoptosis Binding sites Biological Sciences Cell differentiation Crosslinking Crystallography, X-Ray Developmental disabilities Differentiation (biology) Domains Epidermal growth factor Growth factors Humans Jagged-1 Protein - chemistry Jagged-1 Protein - genetics Jagged-1 Protein - metabolism Jagged1 protein Ligands Mass spectrometry Mass spectroscopy Mice Mutation Notch1 protein Protein Binding Protein Interaction Domains and Motifs Receptor, Notch1 - chemistry Receptor, Notch1 - genetics Receptor, Notch1 - metabolism Signalling systems Therapeutic applications X-ray scattering glycoprotein Jagged1 Notch1 cell signaling cross-linking mass spectrometry
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Summary:	The Notch signaling system links cellular fate to that of its neighbors, driving proliferation, apoptosis, and cell differentiation in metazoans, whereas dysfunction leads to debilitating developmental disorders and cancers. Other than a five-by-five domain complex, it is unclear howthe 40 extracellular domains of the Notch1 receptor collectively engage the 19 domains of its canonical ligand, Jagged1, to activate Notch1 signaling. Here, using cross-linking mass spectrometry (XL-MS), biophysical, and structural techniques on the full extracellular complex and targeted sites, we identify five distinct regions, two on Notch1 and three on Jagged1, that form an interaction network. The Notch1 membrane–proximal regulatory region individually binds to the established Notch1 epidermal growth factor (EGF) 8–EGF13 and Jagged1 C2–EGF3 activation sites aswell as to two additional Jagged1 regions, EGF8–EGF11 and cysteine-rich domain. XL-MS and quantitative interaction experiments show that the three Notch1-binding sites on Jagged1 also engage intramolecularly. These interactions, together with Notch1 and Jagged1 ectodomain dimensions and flexibility, determined by small-angle X-ray scattering, support the formation of nonlinear architectures. Combined, the data suggest that critical Notch1 and Jagged1 regions are not distal but engage directly to control Notch1 signaling, thereby redefining the Notch1–Jagged1 activation mechanism and indicating routes for therapeutic applications.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Carol V. Robinson, University of Oxford, Oxford, United Kingdom, and approved June 8, 2021 (received for review February 7, 2021) Author contributions: M.R.Z., R.A.S., and B.J.C.J. designed research; M.R.Z., O.K., J.P.i.d.M., M.J.K., and A.G. performed research; M.R.Z., O.K., R.A.S., and B.J.C.J. analyzed data; and M.R.Z., O.K., R.A.S., and B.J.C.J. wrote the paper. 1M.R.Z. and O.K. contributed equally to this work. 4Present address: NMR Spectroscopy, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands. 3Present address: Vienna BioCenter PhD Program, Doctoral School of the University at Vienna and Medical University of Vienna, 1030 Vienna, Austria. 2Present address: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032.
ISSN:	0027-8424 1091-6490 1091-6490
DOI:	10.1073/pnas.2102502118