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This content will become publicly available on March 2, 2018

Title: Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity

Notch receptor activation initiates cell fate decisions and is distinctive in its reliance on mechanical force and protein glycosylation. The 2.5-angstrom-resolution crystal structure of the extracellular interacting region of Notch1 complexed with an engineered, high-affinity variant of Jagged1 (Jag1) reveals a binding interface that extends ~120 angstroms along five consecutive domains of each protein. O-Linked fucose modifications on Notch1 epidermal growth factor–like (EGF) domains 8 and 12 engage the EGF3 and C2 domains of Jag1, respectively, and different Notch1 domains are favored in binding to Jag1 than those that bind to the Delta-like 4 ligand. Jag1 undergoes conformational changes upon Notch binding, exhibiting catch bond behavior that prolongs interactions in the range of forces required for Notch activation. In conclusion, this mechanism enables cellular forces to regulate binding, discriminate among Notch ligands, and potentiate Notch signaling.
Authors:
ORCiD logo [1] ;  [2] ; ORCiD logo [3] ;  [4] ; ORCiD logo [1] ;  [5] ;  [4] ; ORCiD logo [6] ;  [5] ; ORCiD logo [1]
  1. Stanford Univ., CA (United States). School of Medicine, Dept. of Molecular and Cellular Physiology and Structural Biology; Howard Hughes Medical Inst., Stanford, CA (United States)
  2. Howard Hughes Medical Inst., Baltimore, MD (United States); Johns Hopkins Univ., Baltimore, MD (United States). Dept. of Biomedical Engineering
  3. Georgia Inst. of Technology, Atlanta, GA (United States). Dept. of Biomedical Engineering
  4. Stony Brook Univ., NY (United States). Dept. of Biochemistry and Cell Biology
  5. Howard Hughes Medical Inst., Baltimore, MD (United States); Johns Hopkins Univ., Baltimore, MD (United States). Dept. of Biomedical Engineering; Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine, Dept. of Biophysics and Biophysical Chemistry
  6. Georgia Inst. of Technology, Atlanta, GA (United States). Woodruff School of Mechanical Engineering, Dept. of Biomedical Engineering
Publication Date:
Grant/Contract Number:
AC02-76SF00515; PHY 1430124; R01-GM061126; K99-CA204738; R01-AI044902
Type:
Accepted Manuscript
Journal Name:
Science
Additional Journal Information:
Journal Volume: 355; Journal Issue: 6331; Journal ID: ISSN 0036-8075
Publisher:
AAAS
Research Org:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Science Foundation (NSF); National Institutes of Health (NIH)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES
OSTI Identifier:
1360203