PlexinA1 autoinhibition by the Plexin Sema domain

Semaphorin 3A (Sema3A) binds to neuropilin-1 (NP1) and activates the transm embrane Plexin to transduce a repulsive axon guidance signal. Here, we show that Sema3 signals are transduced equally effectively by PlexinA1 or Plexi nA2, but not by PlexinA3. Deletion analysis of the PlexinA1 ectodomain demo nstrates that the sema domain prevents PlexinA1 activation in the basal sta te. Sema-deleted PlexinA1 is constitutively active, producing cell contract ion, growth cone collapse, and inhibition of neurite outgrowth. The sema do main of PlexinA1 physically associates with the remainder of the PlexinA1 e ctodomain and can reverse constitutive activation. Both the sema portion an d the remainder of the ectodomain of PlexinA1 associate with NP1 in a Sema3 A-independent fashion. Plexin Al is autoinhibited by its sema domain, and S ema3A/NP1 releases this inhibition.