Structural basis of semaphorin-plexin cis interaction.

Daniel Rozbesky,Ross A Robinson,Marieke G Verhagen,Gergely N Nagy,Edith Yvonne Jones,R Jeroen Pasterkamp,Sergi Padilla‐Parra,Dimple Karia,Luis Alvarez,Karl Harlos

doi:10.15252/embj.2019102926

Daniel Rozbesky, Ross A Robinson + Show 8 more

Open Access

https://doi.org/10.15252/embj.2019102926

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Abstract

Semaphorin ligands interact with plexin receptors to contribute to functions in the development of myriad tissues including neurite guidance and synaptic organisation within the nervous system. Cell‐attached semaphorins interact in trans with plexins on opposing cells, but also in cis on the same cell. The interplay between trans and cis interactions is crucial for the regulated development of complex neural circuitry, but the underlying molecular mechanisms are uncharacterised. We have discovered a distinct mode of interaction through which the Drosophila semaphorin Sema1b and mouse Sema6A mediate binding in cis to their cognate plexin receptors. Our high‐resolution structural, biophysical and in vitro analyses demonstrate that monomeric semaphorins can mediate a distinctive plexin binding mode. These findings suggest the interplay between monomeric vs dimeric states has a hereto unappreciated role in semaphorin biology, providing a mechanism by which Sema6s may balance cis and trans functionalities.

Highlights

Semaphorins and plexins are one of the classical cell guidance ligand-receptor families first characterised by their ability to steer axon growth cones in the developing nervous system (Kolodkin et al, 1992, 1993; Luo et al, 1993; Tamagnone et al, 1999)
Cis interactions have been proposed to act as threshold-generating mechanisms for semaphorin-plexin, ephrin–Eph and Notch-Delta signalling during the development of the nervous system (Yaron & Sprinzak, 2012)
Inhibitory cis interactions between Sema6s and PlxnAs have been reported to modulate repulsive cell guidance signalling in a number of neuronal cell types: dorsal root ganglion neurons, spinal cord, starburst amacrine cells in the retina and granule cell axons in the hippocampus (Suto et al, 2007; Renaud et al, 2008; Haklai-Topper et al, 2010; Tawarayama et al, 2010; Sun et al, 2013; Andermatt et al, 2014)

Summary

Introduction

Semaphorins and plexins are one of the classical cell guidance ligand-receptor families first characterised by their ability to steer axon growth cones in the developing nervous system (Kolodkin et al, 1992, 1993; Luo et al, 1993; Tamagnone et al, 1999). In the semaphorin–plexin signalling system, cis interactions were first described between class 6 semaphorins (Sema6s) and their cognate plexin class A (PlxnA) receptors. The inhibitory effect of cis interaction has been demonstrated between Sema6A and PlxnA4 (Haklai-Topper et al, 2010), and Sema6B and PlxnA2 (Andermatt et al, 2014) Contrary to these inhibition effects, the cis interaction between semaphorin SMP-1 and the PlxnA4 homolog, PLX-1, in C. elegans has been shown to result in plexin activation (Mizumoto & Shen, 2013).

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