Neuropilins lock secreted semaphorins onto plexins in a ternary signaling complex

Abstract

Co-receptors add complexity to cell-cell signaling systems. The secreted semaphorin 3s (Sema3s) require a co-receptor, neuropilin (Nrp), to signal through plexin As (PlxnAs) in functions ranging from axon guidance to bone homeostasis, but the co-receptor’s role is obscure. Here we present the low resolution crystal structure of a mouse semaphorin-plexin-Nrp complex alongside unliganded component structures. Dimeric semaphorin, two copies of plexin and two copies of Nrp are arranged as a dimer of heterotrimers. In each heterotrimer sub-complex semaphorin contacts plexin as in co-receptor independent signaling complexes. The Nrp1s cross-brace the assembly, bridging between sema domains of the Sema3A and PlxnA2 subunits from the two heterotrimers. Biophysical and cellular analyses confirm that this Nrp binding mode stabilizes a canonical, but weakened Sema3-PlxnA interaction, adding co-receptor control over the mechanism by which receptor dimerization and/or oligomerization triggers signaling.

The role of the plexin-A2 receptor in semaphorin-3A and semaphorin-3B signal transduction

“…These results suggest again that when plexin-A2 is highly expressed it can transduce Sema3A and Sema3B signals independently of plexin-A4. These results are also in agreement with previous reports showing that at high plexin-A2 expression levels Sema3A can transduce signals through receptors containing complexes of NP1 and plexin-A2 (Janssen et al, 2012). Indeed, we found that Sema3A was able to induce the association of plexin-A2 with NP1 in cells overexpressing plexin-A2, whereas Sema3F was not able to promote such an association (Fig.…”

“…These observations suggest that the Sema3A signaling complex contains these three receptors, an assumption that is supported by coimmunoprecipitation experiments. Because plexin-A2 has also been reported to transduce Sema3A signals and to participate in the formation of functional Sema3A receptors (Takahashi and Strittmatter, 2001;Janssen et al, 2012), we sought to determine whether plexin-A2 also participates in the transduction of Sema3A signals in these cells. To examine this possibility, we inhibited the expression of plexin-A2 in HUVECs and in U87MG cells using two specific shRNA species that do not inhibit the expression of the other class A plexins or the expression of neuropilins ( Fig.…”

“…Interestingly, another study has suggested that plexin-A3 transduces exclusively pro-apoptotic signals of Sema3A but not signals affecting cytoskeletal organization (Ben-Zvi et al, 2008). Additional studies in which plexin-A2 was ectopically expressed at higher expression levels in cells have suggested that plexin-A2 can also transduce Sema3A signals (Janssen et al, 2012;Takahashi and Strittmatter, 2001). Taken together, these observations seem to suggest that all four class A plexins can transduce Sema3A signals, which, in turn, seems to suggest that for Sema3A signaling the class A plexins might be interchangeable.…”

“…However, it should be noted that in most studies using gene-targeted mouse models it is unclear whether the observed loss of responsiveness to Sema3A is due to a direct effect on Sema3A signaling, or whether the targeting affects the expression of a secondary modulator. Likewise, much of the information obtained from cell culture experiments is derived from experiments in which specific plexins were overexpressed, and thus might not be relevant physiologically (Takahashi and Strittmatter, 2001;Janssen et al, 2012).…”

Molecular Mechanisms of Glioma Cell Motility

“…Class 3 semaphorins (Sema3) transfer their function through a receptor complex consisting of plexins and neuropilin (NRP)-1 and -2 (140,141). Downstream signaling of Sema involves RhoA, RAC-1, and cofilin, leading to the reorganization of the cytoskeleton (142).…”