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

Yi-Chun Kuo, Hua Chen, Guijun Shang, Emiko Uchikawa, Hui Tian, Xiao-Chen Bai () and Xuewu Zhang ()
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Yi-Chun Kuo: University of Texas Southwestern Medical Center
Hua Chen: University of Texas Southwestern Medical Center
Guijun Shang: University of Texas Southwestern Medical Center
Emiko Uchikawa: University of Texas Southwestern Medical Center
Hui Tian: University of Texas Southwestern Medical Center
Xiao-Chen Bai: University of Texas Southwestern Medical Center
Xuewu Zhang: University of Texas Southwestern Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15862-0

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