TY - JOUR
T1 - Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity
AU - Luca, Vincent C.
AU - Kim, Byoung Choul
AU - Ge, Chenghao
AU - Kakuda, Shinako
AU - Wu, Di
AU - Roein-Peikar, Mehdi
AU - Haltiwanger, Robert S.
AU - Zhu, Cheng
AU - Ha, Taekjip
AU - Garcia, K. Christopher
N1 - Funding Information:
This work was supported by NIH grant R01-GM097015, a gift from the Mathers Fund, and the Ludwig Cancer Foundation (K.C.G.); the Howard Hughes Medical Institute (K.C.G., T.H., and B.C.K.); a NSF Physics Frontier Center grant (PHY 1430124) (T.H.); an Irvington Postdoctoral Fellowship from the Cancer Research Institute and NIH grant K99-CA204738 (V.C.L); NIH grant R01-AI044902 (C.Z. and C.G); and NIH grant R01-GM061126 (S.K. and R.S.H.).
PY - 2017/3/24
Y1 - 2017/3/24
N2 - 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.
AB - 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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U2 - 10.1126/science.aaf9739
DO - 10.1126/science.aaf9739
M3 - Article
C2 - 28254785
AN - SCOPUS:85014437670
VL - 355
SP - 1320
EP - 1324
JO - Science
JF - Science
SN - 0036-8075
IS - 6331
ER -