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

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Science  02 Mar 2017:
eaaf9739
DOI: 10.1126/science.aaf9739

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Abstract

Notch receptor activation initiates cell fate decisions, and is distinctive in its reliance on mechanical force and protein glycosylation. The 2.5 angstrom crystal structure of the extracellular interacting regions 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 EGF domains 8 and 12 engage the EGF3 and C2 domains of Jag1, respectively, and different Notch domains are favored in binding to Jag1 compared to 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 amongst Notch ligands and potentiate Notch signaling.

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