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

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Science  24 Mar 2017:
Vol. 355, Issue 6331, pp. 1320-1324
DOI: 10.1126/science.aaf9739

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Tugging on Notch receptor tunes signaling

Notch proteins are transmembrane receptors that are important in the regulation of cell fate. They are unusual in that their ligands are membrane-bound on adjacent cells. Luca et al. provide insights into the signaling interactions between Notch and its various ligands. The crystal structure of Notch complexed with a variant of its ligand Jagged1 revealed the interaction of Notch domains containing O-linked glycans with particular domains in Jagged1. Measurements of the effects of various forces on the interaction showed that application of force increases the lifetime of bonds between receptor and ligand. The studies help explain how low-affinity interactions of Notch with its ligands can lead to signaling and indicate that forces may differentially affect Notch-ligand interactions.

Science, this issue p. 1320


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.

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