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. This mechanism enables cellular forces to regulate binding, discriminate among Notch ligands, and potentiate Notch signaling.
authors.affiliation: Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.|Howard Hughes Medical Institute, Stanford, CA 94305, USA.
authors.forename: Vincent C
authors.identifier: 0000-0001-9427-5520
authors.initials: VC
authors.lastname: Luca
authors.affiliation: Howard Hughes Medical Institute, Baltimore, MD 21205, USA.|Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Byoung Choul
authors.initials: BC
authors.lastname: Kim
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: Chenghao
authors.identifier: 0000-0002-1386-3177
authors.initials: C
authors.lastname: Ge
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Shinako
authors.initials: S
authors.lastname: Kakuda
authors.affiliation: Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.|Howard Hughes Medical Institute, Stanford, CA 94305, USA.
authors.forename: Di
authors.identifier: 0000-0001-8409-7046
authors.initials: D
authors.lastname: Wu
authors.affiliation: Howard Hughes Medical Institute, Baltimore, MD 21205, USA.|Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Roein-Peikar
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Haltiwanger
authors.affiliation: Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.|Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: Cheng
authors.identifier: 0000-0002-1718-565X
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Howard Hughes Medical Institute, Baltimore, MD 21205, USA.|Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.|Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Taekjip
authors.initials: T
authors.lastname: Ha
authors.affiliation: Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. kcgarcia@stanford.edu.|Howard Hughes Medical Institute, Stanford, CA 94305, USA.
authors.forename: K Christopher
authors.identifier: 0000-0001-9273-0278
authors.initials: KC
authors.lastname: Garcia
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D005643:Fucose / Q000737:chemistry; D005818:Genetic Engineering; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry; D000072100:Jagged-1 Protein / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry; D011485:Protein Binding; D000072417:Protein Domains; D051381:Rats; D051881:Receptor, Notch1 / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D012441:Saccharomyces cerevisiae; D015398:Signal Transduction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C000606275:Jag1 protein, rat; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; C497763:Notch1 protein, rat; D051881:Receptor, Notch1; C064045:delta protein; D005643:Fucose