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).
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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.
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