Structural insight into Slit-Robo signalling
Structural insight into Slit-Robo signalling
复制标题
DOI：
10.1042/bst0360251
复制
发表时间：
2008-04-01
影响因子：
3.9
通讯作者：
Hohenester, Erhard
中科院分区：
文献类型：
--
作者：
Hohenester, Erhard
果蝇Slit及其脊椎动物同源基因Slit1-Slit3是分泌糖蛋白，在神经系统和其他器官的发育中起重要作用。人类的裂缝也涉及许多病理情况，如癌症和炎症。狭缝通过激活Robo （Roundabout）家族的受体发挥作用，Robo （Roundabout）家族的受体在其外畴类似于细胞粘附分子，具有大的、主要是非结构化的细胞质结构域。HS（硫酸肝素）是狭缝机器人信号所必需的。Slit蛋白的标志是四个LRR（富含亮氨酸的重复）结构域的串联，它们介导与robs的IG（免疫球蛋白样）结构域的结合。一个主要的问题是狭缝结合如何转化为效应分子的招募到Robo的细胞质结构域。详细的结构-功能研究表明，Slit的第二个LRR结构域（D2）与Robo的前两个IG结构域结合，HS用于稳定Slit-Robo相互作用，是Slit D2生物活性所必需的。最近，一个最小的Slit-Robo复合物的晶体结构显示，Robo的IG1结构域与Slit D2的凹面结合，证实了早期的突变数据。为了确定Robo跨膜信号传导的机制，这些结构的见解将必须由新的细胞生物学和显微镜方法来补充。
Drosophila Slit and its vertebrate orthologues Slit1-Slit3 are secreted glycoproteins that play important roles in the development of the nervous system and other organs. Human Slits are also involved in a number of pathological situations, such as cancer and inflammation. Slits exert their effects by activating receptors of the Robo (Roundabout) family, which resemble cell adhesion molecules in their ectodomains and have large, mainly unstructured cytosolic domains. HS (heparan sulfate) is required for Slit-Robo signalling. The hallmark of Slit proteins is a tandem of four LRR (leucine-rich repeat) domains, which mediate binding to the IG (immunoglobulin-like) domains of Robos. A major question is how Slit binding is translated into the recruitment of effector molecules to the cytosolic domain of Robo. Detailed structure-function studies have shown that the second LRR domain of Slit (D2) binds to the first two IG domains of Robo, and that HS serves to stabilize the Slit-Robo interaction and is required for biological activity of Slit D2. Very recently, the crystal structure of a minimal Slit-Robo complex revealed that the IG1 domain of Robo is bound by the concave face of Slit D2, confirming earlier mutagenesis data. To define the mechanism of Robo transmembrane signalling, these structural insights will have to be complemented by new cell biology and microscopy approaches.