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

Abstract

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:
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)
OSTI Identifier:
1360203
Grant/Contract Number:
AC02-76SF00515; PHY 1430124; R01-GM061126; K99-CA204738; R01-AI044902
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Science
Additional Journal Information:
Journal Volume: 355; Journal Issue: 6331; Journal ID: ISSN 0036-8075
Publisher:
AAAS
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

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., 2017. 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. Thu . "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 = {Thu Mar 02 00:00:00 EST 2017},
month = {Thu Mar 02 00:00:00 EST 2017}
}

Journal Article:
Free Publicly Available Full Text
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Cited by: 18works
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  • The following compound, ((CH{sub 3}){sub 4}N)(Cl(dmgBF{sub 2}){sub 2}py), where py = C{sub 5}H{sub 5}N and (dmgBF{sub 2}){sub 2}{sup 2{minus}} = bis((difluoroboryl)dimethyl-glyoximato), was crystallized and its molecular structure determined by X-ray diffraction. The distances between Co(I) and the nitrogen of the macrocycle are unusually short (1.839 {angstrom}), even shorter than the corresponding bond (1.878 {angstrom}) in the cobalt(II) analogue. The cobalt atom is displaced 0.257 {angstrom} above the axial plane toward pyridine. Reasons for this unusual Co-N bond shortening are discussed along with the electronic structure of the d{sup 8} cobalt(I) anion.
  • The initial reaction observed between N-heterocyclic carbene IMes (IMes = 1,3-bis(2,4,6-trimethylphenyl)-imidazol-2-ylidene) and molybdenum and tungsten hydride complexes CpM(CO) 2(PPh 3)H (M = Mo, W) is deprotonation of the metal hydride by IMes, giving [(IMes)H] +[CpM(CO) 2(PPh 3)] . At longer reaction times and higher temperatures, the reaction of IMes with CpM(CO) 2(PR 3)H (M = Mo, W; R = Me, Ph) produces CpM(CO) 2(IMes)H. Hydride transfer from CpW(CO) 2(IMes)H to Ph 3C +B(C 6F 5) 4 - gives CpW(CO) 2(IMes) +B(C 6F 5) 4 - which was crystallographically characterized using x-ray radiation from a synchrotron. The IMes is bondedmore » as a bidentate ligand, through the carbon of the carbene as well as forming a weak bond from the metal to a C =C bond of one mesityl ring. The weakly bound C =C ligand is hemilabile, being readily displaced by H 2, THF, ketones or alcohols. Reaction of CpW(CO) 2(IMes) + with H 2 gives the dihydride complex [CpW(CO) 2(IMes)(H) 2] +. Addition of Et 2CH–OH to CpW(CO) 2(IMes) +B(C 6F 5) 4 - gives the alcohol complex [CpM(CO) 2(IMes)(Et 2CH–OH)] +[B(C 6F 5) 4] which was characterized by crystallography and exhibits no evidence for hydrogen bonding of the bound OH group. Addition of H 2 to the ketone complex [CpW(CO) 2(IMes)(Et 2C =O)] +[B(C 6F 5) 4] produces an equilibrium with the dihydride [CpW(CO) 2(IMes)(H) 2] + (K eq = 1.1 x 103 at 25 °C). The tungsten ketone complex [CpW(CO) 2(IMes)(Et 2C =O)] +[B(C 6F 5) 4] serves as a modest catalyst for hydrogenation of Et 2C =O to Et 2CH–OH in neat ketone solvent. Decomposition of the catalyst produces [H(IMes)] +B(C 6F 5) 4 -, indicating that these catalysts with N-heterocyclic carbenes ligands are vulnerable to decomposition by a reaction that produces a protonated imidazolium cation.« less
  • The initial reaction observed between the N-heterocyclic carbene IMes (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) and molybdenum and tungsten hydride complexes CpM(CO){sub 2}(PPh{sub 3})H (M = Mo, W) is deprotonation of the metal hydride by IMes, giving [(IMes)H]{sup +}[CpM(CO){sub 2}(PPh{sub 3})]{sup -}. At longer reaction times and higher temperatures, the reaction of IMes with CpM(CO){sub 2}(PR{sub 3})H (M = Mo, W; R = Me, Ph) produces CpM(CO){sub 2}(IMes)H. Hydride transfer from CpW(CO)2(IMes)H to Ph{sub 3}C{sub +}B(C{sub 6}F{sub 5}){sub 4}{sup -} gives CpW(CO){sub 2}(IMes){sup +}B(C{sub 6}F{sub 5}){sub 4}{sup -}, which was crystallographically characterized using X-ray radiation from a synchrotron. The IMes is bonded asmore » a bidentate ligand, through the carbon of the carbene as well as forming a weak bond from the metal to a C=C bond of one mesityl ring. The weakly bound C=C ligand is hemilabile, being readily displaced by H{sub 2}, THF, ketones, or alcohols. Reaction of CpW(CO){sub 2}(IMes){sup +} with H{sub 2} gives the dihydride complex [CpW(CO){sub 2}(IMes)(H){sub 2}]{sup +}. Addition of Et{sub 2}CH-OH to CpW(CO){sub 2}(IMes){sup +}B(C{sub 6}F{sub 5}){sub 4}{sup -} gives the alcohol complex [CpW(CO){sub 2}(IMes)(Et{sub 2}CH-OH)]{sup +}[B(C{sub 6}F{sub 5}){sub 4}]{sup -}, which was characterized by crystallography and exhibits no evidence for hydrogen bonding of the bound OH group. Addition of H{sub 2} to the ketone complex [CpW(CO){sub 2}(IMes)(Et{sub 2}C=O)]{sup +}[B(C{sub 6}F{sub 5}){sub 4}]{sup -} produces an equilibrium with the dihydride [CpW(CO){sub 2}(IMes)(H){sub 2}]{sup +} (K{sub eq} = 1.1 x 10{sup 3} at 25 {sup o}C). The tungsten ketone complex [CpW(CO){sub 2}(IMes)(Et{sub 2}C=O)]{sup +}[B(C{sub 6}F{sub 5}){sub 4}]{sup -}- serves as a modest catalyst for hydrogenation of Et{sub 2}C=O to Et{sub 2}CH-OH in neat ketone solvent. Decomposition of the catalyst produces [H(IMes)]{sup +}B(C{sub 6}F{sub 5}){sub 4}{sup -}, indicating that these catalysts with N-heterocyclic carbene ligands are vulnerable to decomposition by a reaction that produces a protonated imidazolium cation.« less