Delta-like (Dll) 1 and Dll4 differently function as Notch ligands in a context-dependent manner. As these ligands share structural properties, the molecular basis for their functional difference is poorly understood. Here, we investigated the superiority of Dll4 over Dll1 with respect to induction of T cell development using a domain-swapping approach in mice. The DOS motif, shared by Notch ligands—except Dll4—contributes to enhancing the activity of Dll for signal transduction. The module at the N-terminus of Notch ligand (MNNL) of Dll4 is inherently advantageous over Dll1. Molecular dynamic simulation revealed that the loop structure in MNNL domain of Dll1 contains unique proline residues with limited range of motion. The Dll4 mutant with Dll1-derived proline residues showed reduced activity. These results suggest that the loop structure—present within the MNNL domain—with a wide range of motion ensures the superiority of Dll4 and uniquely contributes to the triggering of Notch signaling.

中文翻译：

---

Delta-like 1和Delta-like 4不同地需要它们的细胞外域来触发小鼠的Notch信号传导

Delta样（Dll）1和Dll4以依赖于上下文的方式不同地充当Notch配体。由于这些配体具有结构特性，因此对其功能差异的分子基础了解甚少。在这里，我们调查了在域中使用域交换方法诱导T细胞发育方面Dll4优于Dll1的优势。除Dll4外，Notch配体共有的DOS基序有助于增强Dll的信号转导活性。Dll4的Notch配体（MNNL）N端的模块固有地优于Dll1。分子动力学模拟显示，Dll1的MNNL域中的环结构包含运动范围有限的独特脯氨酸残基。具有Dll1衍生的脯氨酸残基的Dll4突变体显示降低的活性。