Structure and Function of Roundabout Receptors.

Francesco Bisiak,Andrew A Mccarthy

doi:10.1007/978-3-030-28151-9_9

Francesco Bisiak, Andrew A Mccarthy

Open Access

https://doi.org/10.1007/978-3-030-28151-9_9

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Abstract

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.

Highlights

Mammalian Robo3 gained the ability to interact with Deleted in Colorectal Cancer (DCC) via its cytoplasmic region (Fig. 9.8), possibly via an adaptor protein, and that Netrin-1 binding to DCC can induce Robo3 phosphorylation to function as a chemoattractive receptor complex (Zelina et al 2014)
While Slit-Robo signalling is conserved in bilateral species, and endocytosis was shown to be important for Slit2 mediated collapse of Xenopus retinal growth cones (Piper et al 2006), no Comm proteins were identified in vertebrates
Robo receptors on the cell surface primarily exist in an auto-inhibited conformation as dimers, or higher oligomers, that can be further stabilized in trans

Summary

Introduction

The hRobo2 structure determined represents an auto-inhibited Robo receptor conformation, with the Robo Ig4 interface shown to be important for dimerization and signalling being sequestered by the FN2 domain (Barak et al 2019) (Fig. 9.5). After midline crossing Comm is downregulated to ensure newly synthesized Robo receptors can reach the cell surface for interaction with Slit to mediate repulsion.

Results

Conclusion