Cryo-EM structure of the PlexinC1/A39R complex reveals inter-domain interactions critical for ligand-induced activation.

Plexins are receptors for semaphorins that transduce signals for regulating neuronal development and other processes. Plexins are single-pass transmembrane proteins with multiple domains in both the extracellular and intracellular regions. Semaphorin activates plexin by binding to its extracellular N-terminal Sema domain, inducing the active dimer of the plexin intracellular region. The mechanism underlying this activation process of plexin is incompletely understood. We present cryo-electron microscopic structure of full-length human PlexinC1 in complex with the viral semaphorin mimic A39R. The structure shows that A39R induces a specific dimer of PlexinC1 where the membrane-proximal domains from the two PlexinC1 protomers are placed close to each other, poised to promote the active dimer of the intracellular region. This configuration is imposed by a distinct conformation of the PlexinC1 extracellular region, stabilized by inter-domain interactions among the Sema and membrane-proximal domains. Our mutational analyses support the critical role of this conformation in PlexinC1 activation. Plexins are the receptors for the guidance molecules semaphorins and regulate immunity and the development of the nervous and cardiovascular systems. Here authors present a structure of full-length human PlexinC1 in complex with its ligand A39R, which reveals how inter-domain interactions couple extracellular ligand binding to receptor activation and signaling.