Structural basis of semaphorin-plexin cis interaction

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 intranswith plexins on opposing cells, but also incison the same cell. The interplay betweentransandcisinteractions 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 theDrosophilasemaphorin Sema1b and mouse Sema6A mediate binding incisto their cognate plexin receptors. Our high-resolution structural, biophysical andin vitroanalyses demonstrate that monomeric semaphorins can mediate a distinctive plexin binding mode. These findings suggest the interplay between monomericvsdimeric states has a hereto unappreciated role in semaphorin biology, providing a mechanism by which Sema6s may balancecisandtransfunctionalities.