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Notch–Jagged signaling complex defined by an interaction mosaic

DOI: 10.1073/pnas.2102502118 DOI Help

Authors: Matthieu R. Zeronian (Utrecht University) , Oleg Klykov (Utrecht University; Netherlands Proteomics Centre) , Júlia Portell I De Montserrat (Utrecht University) , Maria J. Konijnenberg (Utrecht University) , Anamika Gaur (Utrecht University) , Richard A. Scheltema (Utrecht University; Netherlands Proteomics Centre) , Bert Janssen (Utrecht University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 118

State: Published (Approved)
Published: July 2021
Diamond Proposal Number(s): 19800

Abstract: 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 how the 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 as well 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.

Journal Keywords: Notch1; Jagged1; cell signaling; cross-linking mass spectrometry; glycoprotein

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: B21-High Throughput SAXS , I03-Macromolecular Crystallography

Other Facilities: BM29 at ESRF

Added On: 09/08/2021 14:19

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Scattering Macromolecular Crystallography (MX) Small Angle X-ray Scattering (SAXS)