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:
-
[1]
; [2]
; [3]
; [4]
; [1]
; [5]
; [4]
; [6]
; [5]
; [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)
- Howard Hughes Medical Inst., Baltimore, MD (United States); Johns Hopkins Univ., Baltimore, MD (United States). Dept. of Biomedical Engineering
- Georgia Inst. of Technology, Atlanta, GA (United States). Dept. of Biomedical Engineering
- Stony Brook Univ., NY (United States). Dept. of Biochemistry and Cell Biology
- 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
- 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
Luca, Vincent C., Kim, Byoung Choul, Ge, Chenghao, Kakuda, Shinako, Wu, Di, Roein-Peikar, Mehdi, Haltiwanger, Robert S., Zhu, Cheng, Ha, Taekjip, and Garcia, K. Christopher. Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity. United States: N. p.,
Web. doi:10.1126/science.aaf9739.
Luca, Vincent C., Kim, Byoung Choul, Ge, Chenghao, Kakuda, Shinako, Wu, Di, Roein-Peikar, Mehdi, Haltiwanger, Robert S., Zhu, Cheng, Ha, Taekjip, & Garcia, K. Christopher. Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity. United States. doi:10.1126/science.aaf9739.
Luca, Vincent C., Kim, Byoung Choul, Ge, Chenghao, Kakuda, Shinako, Wu, Di, Roein-Peikar, Mehdi, Haltiwanger, Robert S., Zhu, Cheng, Ha, Taekjip, and Garcia, K. Christopher. 2017.
"Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity". United States.
doi:10.1126/science.aaf9739. https://www.osti.gov/servlets/purl/1360203.
@article{osti_1360203,
title = {Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity},
author = {Luca, Vincent C. and Kim, Byoung Choul and Ge, Chenghao and Kakuda, Shinako and Wu, Di and Roein-Peikar, Mehdi and Haltiwanger, Robert S. and Zhu, Cheng and Ha, Taekjip and Garcia, K. Christopher},
abstractNote = {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.},
doi = {10.1126/science.aaf9739},
journal = {Science},
number = 6331,
volume = 355,
place = {United States},
year = {2017},
month = {3}
}
- Free Publicly Accessible Full Text
-
Accepted Manuscript (DOE)
- Publisher's Version of Record
- https://doi.org/10.1126/science.aaf9739
Works referenced in this record:
Coot model-building tools for molecular graphics
journal, November 2004
journal, November 2004
- Emsley, Paul; Cowtan, Kevin
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
journal, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221