Structural basis of semaphorin-plexin recognition and viral mimicry from Sema7A and A39R complexes with PlexinC1.
Repulsive signaling by Semaphorins and Plexins is crucial for the development and homeostasis of the nervous, immune, and cardiovascular systems. Sema7A acts as both an immune and a neural Semaphorin through PlexinC1, and A39R is a Sema7A mimic secreted by smallpox virus. We report the structures of Sema7A and A39R complexed with the Semaphorin-binding module of PlexinC1. Both structures show two PlexinC1 molecules symmetrically bridged by Semaphorin dimers, in which the Semaphorin and PlexinC1 beta propellers interact in an edge-on, orthogonal orientation. Both binding interfaces are dominated by the insertion of the Semaphorin's 4c-4d loop into a deep groove in blade 3 of the PlexinC1 propeller. A39R appears to achieve Sema7A mimicry by preserving key Plexin-binding determinants seen in the mammalian Sema7A complex that have evolved to achieve higher affinity binding to the host-derived PlexinC1. The complex structures support a conserved Semaphorin-Plexin recognition mode and suggest that Plexins are activated by dimerization.
Liu
Heli
H
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Juo
Z Sean
ZS
Shim
Ann Hye-Ryong
AH
Focia
Pamela J
PJ
Chen
Xiaoyan
X
Garcia
K Christopher
KC
He
Xiaolin
X
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D058851:GPI-Linked Proteins; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D055503:Protein Multimerization; D011991:Receptors, Virus / Q000737:chemistry* / Q000378:metabolism; D039961:Semaphorins / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D014616:Vaccinia virus / Q000737:chemistry*; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism
D015703:Antigens, CD; D058851:GPI-Linked Proteins; D011991:Receptors, Virus; C118753:SEMA7A protein, human; D039961:Semaphorins; C112038:VESPR semaphorin receptor; D014764:Viral Proteins