Structural basis for Notch1 engagement of Delta-like 4
Abstract
Notch receptors guide mammalian cell fate decisions by engaging the proteins Jagged and Delta-like (DLL). The 2.3 angstrom resolution crystal structure of the interacting regions of the Notch1-DLL4 complex reveals a two-site, antiparallel binding orientation assisted by Notch1 O-linked glycosylation. Notch1 epidermal growth factor–like repeats 11 and 12 interact with the DLL4 Delta/Serrate/Lag-2 (DSL) domain and module at the N-terminus of Notch ligands (MNNL) domains, respectively. Threonine and serine residues on Notch1 are functionalized with O-fucose and O-glucose, which act as surrogate amino acids by making specific, and essential, contacts to residues on DLL4. Lastly, the elucidation of a direct chemical role for O-glycans in Notch1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites, Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways.
- Authors:
-
- Stanford Univ. School of Medicine, Stanford, CA (United States). Howard Hughes Medical Inst.; Stanford Univ. School of Medicine, Stanford, CA (United States). Dept. of Molecular and Cellular Physiology; Stanford Univ. School of Medicine, Stanford, CA (United States). Dept. of Structural Biology
- Stanford Univ. School of Medicine, Stanford, CA (United States). Dept. of Molecular and Cellular Physiology
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)
- OSTI Identifier:
- 1182315
- Grant/Contract Number:
- AC02-76SF00515; NIH-1RO1-GM097015
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Science
- Additional Journal Information:
- Journal Volume: 347; Journal Issue: 6224; Journal ID: ISSN 0036-8075
- Publisher:
- AAAS
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES
Citation Formats
Luca, Vincent C., Jude, Kevin M., Pierce, Nathan W., Nachury, Maxence V., Fischer, Suzanne, and Garcia, K. Christopher. Structural basis for Notch1 engagement of Delta-like 4. United States: N. p., 2015.
Web. doi:10.1126/science.1261093.
Luca, Vincent C., Jude, Kevin M., Pierce, Nathan W., Nachury, Maxence V., Fischer, Suzanne, & Garcia, K. Christopher. Structural basis for Notch1 engagement of Delta-like 4. United States. https://doi.org/10.1126/science.1261093
Luca, Vincent C., Jude, Kevin M., Pierce, Nathan W., Nachury, Maxence V., Fischer, Suzanne, and Garcia, K. Christopher. Fri .
"Structural basis for Notch1 engagement of Delta-like 4". United States. https://doi.org/10.1126/science.1261093. https://www.osti.gov/servlets/purl/1182315.
@article{osti_1182315,
title = {Structural basis for Notch1 engagement of Delta-like 4},
author = {Luca, Vincent C. and Jude, Kevin M. and Pierce, Nathan W. and Nachury, Maxence V. and Fischer, Suzanne and Garcia, K. Christopher},
abstractNote = {Notch receptors guide mammalian cell fate decisions by engaging the proteins Jagged and Delta-like (DLL). The 2.3 angstrom resolution crystal structure of the interacting regions of the Notch1-DLL4 complex reveals a two-site, antiparallel binding orientation assisted by Notch1 O-linked glycosylation. Notch1 epidermal growth factor–like repeats 11 and 12 interact with the DLL4 Delta/Serrate/Lag-2 (DSL) domain and module at the N-terminus of Notch ligands (MNNL) domains, respectively. Threonine and serine residues on Notch1 are functionalized with O-fucose and O-glucose, which act as surrogate amino acids by making specific, and essential, contacts to residues on DLL4. Lastly, the elucidation of a direct chemical role for O-glycans in Notch1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites, Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways.},
doi = {10.1126/science.1261093},
journal = {Science},
number = 6224,
volume = 347,
place = {United States},
year = {Fri Feb 20 00:00:00 EST 2015},
month = {Fri Feb 20 00:00:00 EST 2015}
}
Web of Science
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