Whiteman, P., de Madrid, B.H., Taylor, P., Li, D., Heslop, R., Viticheep, N., Tan, J.Z., Shimizu, H., Callaghan, J., Masiero, M., Li, J.L., Banham, A.H., Harris, A.L., Lea, S.M., Redfield, C., Baron, M., Handford, P.A. (2013). Molecular basis for jagged-1/serrate ligand recognition by the notch receptor.  J. Biol. Chem. 288(10): 7305--7312.

FBrf0220968

Research paper

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.

PMC3591638 (PMC) (EuropePMC)