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

Journal Article · · Science
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

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.

Research Organization:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Science Foundation (NSF); National Institutes of Health (NIH)
Grant/Contract Number:
AC02-76SF00515
OSTI ID:
1360203
Alternate ID(s):
OSTI ID: 1353229
Journal Information:
Science, Journal Name: Science Journal Issue: 6331 Vol. 355; ISSN 0036-8075
Publisher:
AAASCopyright Statement
Country of Publication:
United States
Language:
English

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Unraveling the mechanism of the cadherin-catenin-actin catch bond journal August 2018
Structural Divergence in O-GlcNAc Glycans Displayed on Epidermal Growth Factor-like Repeats of Mammalian Notch1 journal July 2018
Regulation of genome organization and gene expression by nuclear mechanotransduction journal October 2017
Missense mutation in SLIT2 associated with congenital myopia, anisometropia, connective tissue abnormalities, and obesity text January 2018
Multiple roles for O‐glycans in Notch signalling journal July 2018
A role for actomyosin contractility in Notch signaling journal February 2019
NOTCH Signaling Is Activated through Mechanical Strain in Human Bone Marrow-Derived Mesenchymal Stromal Cells journal February 2019
Somatic mutant clones colonize the human esophagus with age journal October 2018
Mechanotransduction in T Cell Development, Differentiation and Function journal February 2020
Intriguing Roles for Endothelial ADAM10/Notch Signaling in the Development of Organ-Specific Vascular Beds journal October 2018
Long-range Notch-mediated tissue patterning requires actomyosin contractility posted_content February 2018
Structural and functional dissection of the interplay between lipid and Notch binding by human Notch ligands journal January 2017
Force transduction by cadherin adhesions in morphogenesis journal January 2019
Regulation of Notch Function by O-Glycosylation book January 2018
Influence of the Assembly State on the Functionality of a Supramolecular Jagged1-Mimicking Peptide Additive journal May 2019
KSHV and the Role of Notch Receptor Dysregulation in Disease Progression journal August 2017
Vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic stress journal August 2019
A brighter force gauge for cells journal July 2018
Molecular engineering strategies for visualizing low-affinity protein complexes journal June 2019
Pofut1 point-mutations that disrupt O-fucosyltransferase activity destabilize the protein and abolish Notch1 signaling during mouse somitogenesis journal November 2017
Mutual regulation of JAG2 and PRAF2 promotes migration and invasion of colorectal cancer cells uncoupled from epithelial–mesenchymal transition journal June 2019
Fibronectin-dependent tissue mechanics regulate the translation of segmentation clock oscillations into periodic somite formation posted_content December 2019
Comparison of T Cell Activities Mediated by Human TCRs and CARs That Use the Same Recognition Domains journal December 2017
Biophysical nanotools for single-molecule dynamics journal August 2018
The ectodomains determine ligand function in vivo and selectivity of DLL1 and DLL4 toward NOTCH1 and NOTCH2 in vitro journal October 2018
The sugar code: letters and vocabulary, writers, editors and readers and biosignificance of functional glycan–lectin pairing journal September 2019
Missense mutation in SLIT2 associated with congenital myopia, anisometropia, connective tissue abnormalities, and obesity journal August 2018
Unraveling the mechanism of the cadherin-catenin-actin catch bond journal August 2018
Mechanisms of Notch signaling: a simple logic deployed in time and space journal February 2019
ADAM10 controls the differentiation of the coronary arterial endothelium journal November 2018
Uncontrolled angiogenic precursor expansion causes coronary artery anomalies in mice lacking Pofut1 journal September 2017
Somatic mutant clones colonize the human esophagus with age. text January 2018
Receptor-mediated cell mechanosensing journal November 2017
Distinctive properties of the interactions between Notch and Notch ligands journal December 2019
Structural Insights into Notch Receptor-Ligand Interactions book July 2018
O -Glycosylation modulates the stability of epidermal growth factor-like repeats and thereby regulates Notch trafficking journal July 2017
Penicilazaphilone C, a New Azaphilone, Induces Apoptosis in Gastric Cancer by Blocking the Notch Signaling Pathway journal February 2020
Mutual regulation of JAG2 and PRAF2 promotes migration and invasion of colorectal cancer cells uncoupled from epithelial–mesenchymal transition journal June 2019
Interleukin-22 attenuates renal tubular cells inflammation and fibrosis induced by TGF-β1 through Notch1 signaling pathway journal January 2020
Biological functions of fucose in mammals journal May 2017
Role of NOTCH3 Mutations in the Cerebral Small Vessel Disease Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy journal November 2018
Unraveling the mechanism of the cadherin-catenin-actin catch bond posted_content April 2018
Receptor-mediated cell mechanosensing journal November 2017
Making sense out of missense mutations: Mechanistic dissection of Notch receptors through structure‐function studies in Drosophila journal December 2019
Spatial patterning of liver progenitor cell differentiation mediated by cellular contractility and Notch signaling journal December 2018
Vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic stress journal August 2019
Glycosylation of Specific Notch EGF Repeats by O-Fut1 and Fringe Regulates Notch Signaling in Drosophila journal November 2019
Mechanosensitivity of Jagged–Notch signaling can induce a switch-type behavior in vascular homeostasis journal April 2018
Novel JAG1 Deletion Variant in Patient with Atypical Alagille Syndrome journal December 2019
The ectodomains determine ligand function in vivo and selectivity of DLL1 and DLL4 toward NOTCH1 and NOTCH2 in vitro journal October 2018
Mechanosensitivity of Jagged–Notch signaling can induce a switch-type behavior in vascular homeostasis text January 2018
A perspective on structural and mechanistic aspects of protein O -fucosylation journal July 2018
Missense mutation in SLIT2 associated with congenital myopia, anisometropia, connective tissue abnormalities, and obesity journal August 2018
Tensile and compressive force regulation on cell mechanosensing journal May 2019
Mechanosensing through immunoreceptors journal September 2019
DLK proteins modulate NOTCH signaling to influence a brown or white 3T3-L1 adipocyte fate journal November 2018
The Molecular Mechanism of Notch Activation book January 2018
DNA Nanotechnology as an Emerging Tool to Study Mechanotransduction in Living Systems journal February 2019
Notch Signaling in Development, Tissue Homeostasis, and Disease journal October 2017
Novel JAG1 Deletion Variant in Patient with Atypical Alagille Syndrome journal December 2019
Force transduction by cadherin adhesions in morphogenesis journal January 2019
A modifier in the 129S2/SvPasCrl genome is responsible for the viability of Notch1[12f/12f] mice journal October 2019
Effects of Notch glycosylation on health and diseases journal December 2019