Bisiak Francesco, McCarthy Andrew A
European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue Des Martyrs, 38042, Grenoble, France.
Subcell Biochem. 2019;93:291-319. doi: 10.1007/978-3-030-28151-9_9.
The creation of complex neuronal networks relies on ligand-receptor interactions that mediate attraction or repulsion towards specific targets. Roundabouts comprise a family of single-pass transmembrane receptors facilitating this process upon interaction with the soluble extracellular ligand Slit protein family emanating from the midline. Due to the complexity and flexible nature of Robo receptors , their overall structure has remained elusive until now. Recent structural studies of the Robo 1 and Robo 2 ectodomains have provided the basis for a better understanding of their signalling mechanism. These structures reveal how Robo receptors adopt an auto-inhibited conformation on the cell surface that can be further stabilised by cis and/or trans oligmerisation arrays. Upon Slit -N binding Robo receptors must undergo a conformational change for Ig4 mediated dimerisation and signaling, probably via endocytosis. Furthermore, it's become clear that Robo receptors do not only act alone, but as large and more complex cell surface receptor assemblies to manifest directional and growth effects in a concerted fashion. These context dependent assemblies provide a mechanism to fine tune attractive and repulsive signals in a combinatorial manner required during neuronal development. While a mechanistic understanding of Slit mediated Robo signaling has advanced significantly further structural studies on larger assemblies are required for the design of new experiments to elucidate their role in cell surface receptor complexes. These will be necessary to understand the role of Slit -Robo signaling in neurogenesis, angiogenesis, organ development and cancer progression. In this chapter, we provide a review of the current knowledge in the field with a particular focus on the Roundabout receptor family.
复杂神经元网络的形成依赖于配体-受体相互作用，这种相互作用介导对特定靶点的吸引或排斥。Roundabouts是一类单次跨膜受体家族，在与从中线发出的可溶性细胞外配体Slit蛋白家族相互作用时促进这一过程。由于Robo受体的复杂性和灵活性质，其整体结构至今仍不清楚。最近对Robo 1和Robo 2胞外域的结构研究为更好地理解其信号传导机制提供了基础。这些结构揭示了Robo受体如何在细胞表面采取一种自抑制构象，这种构象可以通过顺式和/或反式寡聚化阵列进一步稳定。在Slit -N结合时，Robo受体必须经历构象变化以实现Ig4介导的二聚化和信号传导，可能是通过内吞作用。此外，很明显Robo受体不仅单独起作用，而且作为更大、更复杂的细胞表面受体组装体以协同方式表现出定向和生长效应。这些依赖于背景的组装体提供了一种机制，以组合方式微调神经元发育过程中所需的吸引和排斥信号。虽然对Slit介导的Robo信号传导的机制理解有了显著进展，但对于阐明其在细胞表面受体复合物中的作用的新实验设计，仍需要对更大组装体进行进一步的结构研究。这些对于理解Slit -Robo信号传导在神经发生、血管生成、器官发育和癌症进展中的作用将是必要的。在本章中，我们对该领域的当前知识进行了综述，特别关注Roundabout受体家族。
