A Tail of Two Sites: A Bipartite Mechanism for Recognition of Notch Ligands by Mind Bomb E3 Ligases
A Tail of Two Sites: A Bipartite Mechanism for Recognition of Notch Ligands by Mind Bomb E3 Ligases
复制标题
DOI：
10.1016/j.molcel.2015.01.019
复制
发表时间：
2015-03-05
期刊：
影响因子：
16
通讯作者：
Blacklow, Stephen C.
中科院分区：
文献类型：
--
作者：
McMillan, Brian J.;Schnute, Bjoern;Blacklow, Stephen C.
思维炸弹（Mib）蛋白是大的多结构域E3连接酶，其促进Notch配体的胞质尾的泛素化。该泛素化步骤标记了用于胰蛋白酶依赖性内吞作用的配体蛋白，这对于体内Notch受体活化是关键的。我们在这里提出的Mib 1的底物识别结构域的晶体结构，无论是在隔离和复杂的肽来自Notch配体。结合生物化学，细胞，和体内试验的结构，表明Mib 1包含两个独立的底物识别域，从事两个不同的表位从配体锯齿状1，一个在细胞内膜近端区域和其他附近的C末端的胞质尾。总之，这些研究提供了对思维炸弹E3连接酶的泛素转移机制的见解，阐明了配体诱导的Notch受体激活中的关键事件，并确定了疾病中Notch信号转导治疗调节的潜在靶点。
Mind bomb (Mib) proteins are large, multi-domain E3 ligases that promote ubiquitination of the cytoplasmic tails of Notch ligands. This ubiquitination step marks the ligand proteins for epsin-dependent endocytosis, which is critical for in vivo Notch receptor activation. We present here crystal structures of the substrate recognition domains of Mib1, both in isolation and in complex with peptides derived from Notch ligands. The structures, in combination with biochemical, cellular, and in vivo assays, show that Mib1 contains two independent substrate recognition domains that engage two distinct epitopes from the cytoplasmic tail of the ligand Jagged1, one in the intracellular membrane proximal region and the other near the C terminus. Together, these studies provide insights into the mechanism of ubiquitin transfer by Mind bomb E3 ligases, illuminate a key event in ligand-induced activation of Notch receptors, and identify a potential target for therapeutic modulation of Notch signal transduction in disease.