Forces on Notch receptors can modulate receptor signaling. 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.

中文翻译：

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Notch-Jagged 复杂结构涉及调节配体敏感性的捕获键

Notch 受体上的力可以调节受体信号。拉动 Notch 受体信号的信号 Notch 蛋白是跨膜受体，在细胞命运的调节中很重要。它们的不同寻常之处在于它们的配体与相邻细胞膜结合。卢卡等人。深入了解 Notch 及其各种配体之间的信号相互作用。Notch 的晶体结构与其配体 Jagged1 的变体复合，揭示了含有 O-连接聚糖的 Notch 域与 Jagged1 中特定域的相互作用。各种力对相互作用影响的测量表明，力的应用增加了受体和配体之间键的寿命。这些研究有助于解释 Notch 与其配体的低亲和力相互作用如何导致信号传导，并表明力可能会不同地影响 Notch-配体相互作用。科学，这个问题 p。1320 Notch 受体激活启动细胞命运决定，其独特之处在于它依赖于机械力和蛋白质糖基化。Notch1 细胞外相互作用区的 2.5 埃分辨率晶体结构与 Jagged1 (Jag1) 的工程化高亲和力变体复合，揭示了一个结合界面，该界面沿每个蛋白质的五个连续域延伸约 120 埃。Notch1 表皮生长因子样 (EGF) 域 8 和 12 上的 O-Linked 岩藻糖修饰分别与 Jag1 的 EGF3 和 C2 域结合，和与 Delta-like 4 配体结合的结构域相比，不同的 Notch1 结构域更有利于与 Jag1 结合。Jag1 在 Notch 结合后发生构象变化，表现出捕获键行为，延长了 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 配体并加强 Notch 信号传导。