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Abstract
Secreted class 3 semaphorins (Sema3s) form tripartite complexes with the plexin receptor and neuropilin coreceptor, which are both transmembrane proteins that together mediate semaphorin signal for neuronal axon guidance and other processes. Despite extensive investigations, the overall architecture of and the molecular interactions in the Sema3/plexin/neuropilin complex are incompletely understood. Here we present the cryo-EM structure of a near intact extracellular region complex of Sema3A, PlexinA4 and Neuropilin 1 (Nrp1) at 3.7 Å resolution. The structure shows a large symmetric 2:2:2 assembly in which each subunit makes multiple interactions with others. The two PlexinA4 molecules in the complex do not interact directly, but their membrane proximal regions are close to each other and poised to promote the formation of the intracellular active dimer for signaling. The structure reveals a previously unknown interface between the a2b1b2 module in Nrp1 and the Sema domain of Sema3A. This interaction places the a2b1b2 module at the top of the complex, far away from the plasma membrane where the transmembrane regions of Nrp1 and PlexinA4 embed. As a result, the region following the a2b1b2 module in Nrp1 must span a large distance to allow the connection to the transmembrane region, suggesting an essential role for the long non-conserved linkers and the MAM domain in neuropilin in the semaphorin/plexin/neuropilin complex.
Secreted class 3 semaphorins (Sema3s) form tripartite complexes with a plexin receptor and neuropilin co-receptor to transduce signals for neuronal axon guidance and other processes. Here, the authors present the cryo-EM structure of the extracellular Sema3A/PlexinA4/Neuropilin1 complex that provides further insights into the interactions among semaphorin, plexin and neuropilin and reveals long flexible linkers in semaphorin and neuropilin that are important for complex formation.
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1 University of Texas Southwestern Medical Center, Department of Pharmacology, Dallas, USA (GRID:grid.267313.2) (ISNI:0000 0000 9482 7121)
2 College of Life Science and Technology, Huazhong University of Science and Technology, Key Laboratory of Molecular Biophysics of the Ministry of Education, Wuhan, China (GRID:grid.33199.31) (ISNI:0000 0004 0368 7223)
3 University of Texas Southwestern Medical Center, Department of Biophysics, Dallas, USA (GRID:grid.267313.2) (ISNI:0000 0000 9482 7121); University of Texas Southwestern Medical Center, Department of Cell Biology, Dallas, USA (GRID:grid.267313.2) (ISNI:0000 0000 9482 7121)
4 University of Texas Southwestern Medical Center, Department of Pharmacology, Dallas, USA (GRID:grid.267313.2) (ISNI:0000 0000 9482 7121); University of Texas Southwestern Medical Center, Department of Biophysics, Dallas, USA (GRID:grid.267313.2) (ISNI:0000 0000 9482 7121)