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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 Robo1 and Robo2 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.

Many bacteria encode multiple toxin-antitoxin (TA) systems targeting separate, but closely related, cellular functions. The toxin of the E. coli hipBA system, HipA, is a kinase that inhibits inhibits translation via phosphorylation of glutamyl-tRNA synthetase. Enteropathogenic E. coli (EPEC) O127:H6 encodes an additional, tripartite TA module, hipBST, for which the HipT toxin was shown to specifically target tryptophanyl-tRNA synthetase, TrpS. Surprisingly, the function as antitoxin has been taken over by the third protein, HipS, but the molecular details of how activity of HipT is controlled remain poorly understood. Here, we show that HipBST is markedly different from HipBA and that the unique HipS protein, which is homologous to the N-terminal subdomain of HipA, has evolved to function as antitoxin by breaking the kinase active site. We also show how auto-phosphorylation at two conserved sites in the kinase toxin serve to dually regulate binding of HipS and kinase activity. Finally, we demonstrate that the HipBST complex is dynamic and present a cohesive model for the regulation and activation of this type of three-component system.

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