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Title: 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:
 [1];  [1];  [2];  [2];  [1];  [1]
  1. 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
  2. Stanford Univ. School of Medicine, Stanford, CA (United States). Dept. of Molecular and Cellular Physiology
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); 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. doi: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. doi: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 = {2015},
month = {2}
}

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Cited by: 63 works
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Works referenced in this record:

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    Works referencing / citing this record:

    X-Ray Diffraction data from Complex of Notch1 (EGF11-13) bound to Delta-like 4 (N-EGF2) , source of 4XLW structure
    dataset, May 2015

    • Luca, Vincent C.; Jude, Kevin M.; Garcia, K. Christopher
    • SBGrid Data Bank
    • DOI: 10.15785/sbgrid/69

    Jagged1 ( JAG1 ) mutations in Alagille syndrome: increasing the mutation detection rate
    journal, May 2006

    • Warthen, Dm; Moore, Ec; Kamath, Bm
    • Human Mutation, Vol. 27, Issue 5
    • DOI: 10.1002/humu.20310

    A secreted Delta1-Fc fusion protein functions both as an activator and inhibitor of Notch1 signaling
    journal, May 2002

    • Hicks, Carol; Ladi, Ena; Lindsell, Claire
    • Journal of Neuroscience Research, Vol. 68, Issue 6
    • DOI: 10.1002/jnr.10263

    A Noncommercial Dual Luciferase Enzyme Assay System for Reporter Gene Analysis
    journal, June 2000

    • Dyer, Benjamin W.; Ferrer, Fernando A.; Klinedinst, Donna K.
    • Analytical Biochemistry, Vol. 282, Issue 1
    • DOI: 10.1006/abio.2000.4605

    Solution structure of an EGF module pair from the Plasmodium falciparum merozoite surface protein 1 1 1Edited by P. E. Wright
    journal, May 1999

    • Morgan, William D.; Birdsall, Berry; Frenkiel, Thomas A.
    • Journal of Molecular Biology, Vol. 289, Issue 1
    • DOI: 10.1006/jmbi.1999.2753

    Structural conservation of Notch receptors and ligands
    journal, December 1998


    Specific EGF repeats of Notch mediate interactions with Delta and serrate: Implications for notch as a multifunctional receptor
    journal, November 1991


    Rumi Is a CAP10 Domain Glycosyltransferase that Modifies Notch and Is Required for Notch Signaling
    journal, January 2008


    The Notch Ligands Dll4 and Jagged1 Have Opposing Effects on Angiogenesis
    journal, June 2009


    The Conserved Bardet-Biedl Syndrome Proteins Assemble a Coat that Traffics Membrane Proteins to Cilia
    journal, June 2010


    Structural Analysis Uncovers Lipid-Binding Properties of Notch Ligands
    journal, November 2013


    Inference of Macromolecular Assemblies from Crystalline State
    journal, September 2007


    Fringe benefits: Functional and structural impacts of O-glycosylation on the extracellular domain of Notch receptors
    journal, October 2011

    • Rana, Nadia A.; Haltiwanger, Robert S.
    • Current Opinion in Structural Biology, Vol. 21, Issue 5
    • DOI: 10.1016/j.sbi.2011.08.008

    Notch signaling in development and disease
    journal, October 2004


    Structural and Functional Properties of the Human Notch-1 Ligand Binding Region
    journal, December 2004


    Lysine Methylation as a Routine Rescue Strategy for Protein Crystallization
    journal, November 2006


    Generation of anti-Notch antibodies and their application in blocking Notch signalling in neural stem cells
    journal, September 2012


    A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain
    journal, April 1999

    • De Strooper, Bart; Annaert, Wim; Cupers, Philippe
    • Nature, Vol. 398, Issue 6727
    • DOI: 10.1038/19083

    Presenilin is required for activity and nuclear access of Notch in Drosophila
    journal, April 1999

    • Struhl, Gary; Greenwald, Iva
    • Nature, Vol. 398, Issue 6727
    • DOI: 10.1038/19091

    Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2
    journal, July 2000

    • Hicks, Carol; Johnston, Stuart H.; diSibio, Guy
    • Nature Cell Biology, Vol. 2, Issue 8
    • DOI: 10.1038/35019553

    Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia
    journal, October 1996

    • Joutel, Anne; Corpechot, Christophe; Ducros, Anne
    • Nature, Vol. 383, Issue 6602
    • DOI: 10.1038/383707a0

    Fringe modulates Notch–ligand interactions
    journal, June 1997

    • Panin, Vladislav M.; Papayannopoulos, Venizelos; Wilson, Richa
    • Nature, Vol. 387, Issue 6636
    • DOI: 10.1038/43191

    Mutations in NOTCH1 cause aortic valve disease
    journal, July 2005

    • Garg, Vidu; Muth, Alecia N.; Ransom, Joshua F.
    • Nature, Vol. 437, Issue 7056
    • DOI: 10.1038/nature03940

    Therapeutic antibody targeting of individual Notch receptors
    journal, April 2010


    Cis-interactions between Notch and Delta generate mutually exclusive signalling states
    journal, April 2010

    • Sprinzak, David; Lakhanpal, Amit; LeBon, Lauren
    • Nature, Vol. 465, Issue 7294
    • DOI: 10.1038/nature08959

    Isolating and engineering human antibodies using yeast surface display
    journal, July 2006

    • Chao, Ginger; Lau, Wai L.; Hackel, Benjamin J.
    • Nature Protocols, Vol. 1, Issue 2
    • DOI: 10.1038/nprot.2006.94

    Protein structure prediction on the Web: a case study using the Phyre server
    journal, February 2009

    • Kelley, Lawrence A.; Sternberg, Michael J. E.
    • Nature Protocols, Vol. 4, Issue 3
    • DOI: 10.1038/nprot.2009.2

    Cis interactions of immunoreceptors with MHC and non-MHC ligands
    journal, February 2008

    • Held, Werner; Mariuzza, Roy A.
    • Nature Reviews Immunology, Vol. 8, Issue 4
    • DOI: 10.1038/nri2278

    Regulation of innate and adaptive immunity by Notch
    journal, May 2013

    • Radtke, Freddy; MacDonald, H. Robson; Tacchini-Cottier, Fabienne
    • Nature Reviews Immunology, Vol. 13, Issue 6
    • DOI: 10.1038/nri3445

    A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition
    journal, July 2008

    • Cordle, Jemima; Johnson, Steven; Zi Yan Tay, Joyce
    • Nature Structural & Molecular Biology, Vol. 15, Issue 8
    • DOI: 10.1038/nsmb.1457

    Structural basis for autoinhibition of Notch
    journal, April 2007

    • Gordon, Wendy R.; Vardar-Ulu, Didem; Histen, Gavin
    • Nature Structural & Molecular Biology, Vol. 14, Issue 4
    • DOI: 10.1038/nsmb1227

    The many facets of Notch ligands
    journal, September 2008


    Notch signaling represents an important checkpoint between follicular T-helper and canonical T-helper 2 cell fate
    journal, February 2018


    Receptor subtype discrimination using extensive shape complementary designed interfaces
    journal, May 2019


    Jagged1 signals in the postnatal subventricular zone are required for neural stem cell self-renewal
    journal, September 2005


    Fringe-mediated extension of O-linked fucose in the ligand-binding region of Notch1 increases binding to mammalian Notch ligands
    journal, May 2014

    • Taylor, P.; Takeuchi, H.; Sheppard, D.
    • Proceedings of the National Academy of Sciences, Vol. 111, Issue 20
    • DOI: 10.1073/pnas.1319683111

    Fringe modulation of Jagged1-induced Notch signaling requires the action of  4galactosyltransferase-1
    journal, November 2001

    • Chen, J.; Moloney, D. J.; Stanley, P.
    • Proceedings of the National Academy of Sciences, Vol. 98, Issue 24
    • DOI: 10.1073/pnas.241398098

    The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands
    journal, September 2005

    • Ladi, Ena; Nichols, James T.; Ge, Weihong
    • The Journal of Cell Biology, Vol. 170, Issue 6
    • DOI: 10.1083/jcb.200503113

    DSL ligand endocytosis physically dissociates Notch1 heterodimers before activating proteolysis can occur
    journal, February 2007

    • Nichols, James T.; Miyamoto, Alison; Olsen, Samantha L.
    • The Journal of Cell Biology, Vol. 176, Issue 4
    • DOI: 10.1083/jcb.200609014

    NOTCH2 Mutations Cause Alagille Syndrome, a Heterogeneous Disorder of the Notch Signaling Pathway
    journal, July 2006

    • McDaniell, Ryan; Warthen, Daniel M.; Sanchez-Lara, Pedro A.
    • The American Journal of Human Genetics, Vol. 79, Issue 1
    • DOI: 10.1086/505332

    The DynDom database of protein domain motions
    journal, July 2003


    Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia
    journal, October 2004


    Structural Basis of Wnt Recognition by Frizzled
    journal, May 2012


    A Mutation in EGF Repeat-8 of Notch Discriminates Between Serrate/Jagged and Delta Family Ligands
    journal, November 2012


    Cholesterol Modification of Hedgehog Signaling Proteins in Animal Development
    journal, October 1996


    Notch Signaling: Cell Fate Control and Signal Integration in Development
    journal, April 1999


    The Notch1-Dll4 signaling pathway regulates mouse postnatal lymphatic development
    journal, August 2011


    Crystal Structure of Reovirus Attachment Protein σ1 in Complex with Sialylated Oligosaccharides
    journal, August 2011