Luca Vincent C, Kim Byoung Choul, Ge Chenghao, Kakuda Shinako, Wu Di, Roein-Peikar Mehdi, Haltiwanger Robert S, Zhu Cheng, Ha Taekjip, Garcia K Christopher
Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Howard Hughes Medical Institute, Stanford, CA 94305, USA.
Science. 2017 Mar 24;355(6331):1320-1324. doi: 10.1126/science.aaf9739. Epub 2017 Mar 2.
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. -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.
Notch受体激活引发细胞命运决定，其独特之处在于依赖机械力和蛋白质糖基化。与工程化的高亲和力Jagged1（Jag1）变体复合的Notch1细胞外相互作用区域的2.5埃分辨率晶体结构揭示了一个结合界面，该界面沿着每种蛋白质的五个连续结构域延伸约120埃。Notch1表皮生长因子样（EGF）结构域8和12上的岩藻糖修饰分别与Jag1的EGF3和C2结构域结合，与结合Delta样4配体的结构域相比，Notch1的不同结构域更倾向于与Jag1结合。Jag1在与Notch结合后会发生构象变化，表现出捕获键行为，这种行为会延长Notch激活所需力范围内的相互作用。这种机制使细胞力能够调节结合、区分Notch配体并增强Notch信号传导。
