The Notch-Jagged complex structure

Chris Garcia group (Stanford University)

In a study on cell-to-cell interactions, the group of Chris Garcia at Stanford University and collaborators determined the first crystal structure of the Notch1 receptor in complex with its Jagged1 (Jag1) ligand. Activation of Notch receptors by the ligands Delta-like and Jagged guides cell fate decisions in all metazoans, and mutations in the Notch pathway contribute to pathogenesis in many cancers. In mammals, Notch signaling requires molecular tension between Notch- and Jagged-expressing cells and is fine tuned by changes in the receptor glycosylation state. To stabilize the complex of weak binding partners, affinity-enhancing mutations were introduced in Jag1 by directed evolution. Five domains in each of Notch1 and Jag1 form a long, narrow interface. Multiple Notch1 side chains with O-linked fucose modifications contact Jag1, demonstrating how Notch glycosylation influences signaling. Single-molecule experiments indicated that Notch1 and Jag1 form 'catch bonds' with prolonged lifetimes. Catch-bond formation appears mediated by hinge-like motions of Jag1 domains. In the structure, the affinity-enhancing mutations stabilize a "bent" receptor-bound conformation of Jag1. In the proposed mechanism, force-induced structural changes enable ligands to overcome intrinsically low affinities for Notch receptors and in turn trigger downstream signaling. The figure shows the Notch1 (magenta) - Jagg1 (green) complex juxtaposed with original documentation of the Drosophila "notched wing" phenotype for which the Notch receptor was named (identified by John Dexter in 1914 and Thomas Morgan in 1917).

Five domains in each of Notch1 and Jag1 form a long, narrow interface.

Luca, VC, Kim, BC, Ge, C, Kakuda, S, Wu, D, Roein-Peikar, M, Haltiwanger, RS, Zhu, C, Ha, T, Garcia, KC, "Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity," Science 355, 1320-1324 (2017). DOI: 10.1126/science.aaf9739.