title: Molecular basis for Jagged-1/Serrate ligand recognition by the Notch receptor.
abstract: We have mapped a Jagged/Serrate-binding site to specific residues within the 12th EGF domain of human and Drosophila Notch. Two critical residues, involved in a hydrophobic interaction, provide a ligand-binding platform and are adjacent to a Fringe-sensitive residue that modulates Notch activity. Our data suggest that small variations within the binding site fine-tune ligand specificity, which may explain the observed sequence heterogeneity in mammalian Notch paralogues, and should allow the development of paralogue-specific ligand-blocking antibodies. As a proof of principle, we have generated a Notch-1-specific monoclonal antibody that blocks binding, thus paving the way for antibody tools for research and therapeutic applications.
authors: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
authors: Pat
authors: P
authors: Whiteman
authors: Beatriz Hernandez
authors: BH
authors: de Madrid
authors: Paul
authors: P
authors: Taylor
authors: Demin
authors: D
authors: Li
authors: Rebecca
authors: R
authors: Heslop
authors: Nattnee
authors: N
authors: Viticheep
authors: Joyce Zi
authors: JZ
authors: Tan
authors: Hideyuki
authors: H
authors: Shimizu
authors: Juliana
authors: J
authors: Callaghan
authors: Massimo
authors: M
authors: Masiero
authors: Ji Liang
authors: JL
authors: Li
authors: Alison H
authors: AH
authors: Banham
authors: Adrian L
authors: AL
authors: Harris
authors: Susan M
authors: SM
authors: Lea
authors: Christina
authors: C
authors: Redfield
authors: Martin
authors: M
authors: Baron
authors: Penny A
authors: PA
authors: Handford
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051880:Receptors, Notch / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D000072099:Serrate-Jagged Proteins
chemical_list: D000911:Antibodies, Monoclonal; D002135:Calcium-Binding Proteins; D029721:Drosophila Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D051881:Receptor, Notch1; D051880:Receptors, Notch; C000606278:Ser protein, Drosophila; D000072099:Serrate-Jagged Proteins