(VESPR) binds Sema7A, consistent with the observation that Sema7A is the host semaphorin that shares the greatest sequence similarity to viral semaphorins. The class 3 semaphorins, including Sema3A, Sema3C, and Sema3F, bind directly to NPs but do not bind to Plex family members. Nonetheless, NP-1 and Plex-A1 form a complex with enhanced affinity for Sema3A (8, 9). Plex proteins are now thought to constitute a signaling moiety in a receptor complex for the class 3 semaphorins, where NPs provide the ligand-binding sites. Recent data suggest that Plex-A1 is subject to autoinhibition mediated by its intrinsic Sema domain (10). Sema-deleted Plex-A1 is constitutively active, producing cell contraction, growth cone collapse, and inhibition of neurite outgrowth. This Sema domain of Plex-A1 physically associates with the remainder of the Plex-A1 ectodomain and can act in trans to reverse constitutive activation. Both the Sema portion and the remainder of the ectodomain of Plex-A1 associate with NP-1 in a Sema3A-independent fashion. Hence, it appears that Plex-A1 is autoinhibited by its Sema domain but that Sema3A/NP-1 releases this inhibition.