Department of Immunology, Tokai University School of Medicine, Isehara, Japan.
Department of Bioinformatics, Graduate School of Medicine, Chiba University, Chiba, Japan.
Elife. 2020 Jan 16;9:e50979. doi: 10.7554/eLife.50979.
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.
Delta-like (Dll) 1 和 Dll4 以依赖于上下文的方式作为 Notch 配体发挥不同的功能。由于这些配体具有结构相似性，因此它们在功能上的差异的分子基础还了解甚少。在这里，我们通过在小鼠中进行结构域交换的方法，研究了 Dll4 相对于 Dll1 在诱导 T 细胞发育方面的优势。除了 Dll4 之外，Notch 配体所共享的 DOS 基序有助于增强 Dll 用于信号转导的活性。Dll4 的 Notch 配体 N 端模块（MNNL）在固有优势上优于 Dll1。分子动力学模拟表明，Dll1 中的 MNNL 结构域中的环结构含有独特的脯氨酸残基，其运动范围有限。具有 Dll1 衍生脯氨酸残基的 Dll4 突变体显示出活性降低。这些结果表明，存在于 MNNL 结构域中的环结构具有广泛的运动范围，确保了 Dll4 的优越性，并独特地有助于触发 Notch 信号。
