Plexin A4 is a 220-230kD member of the plexin A subfamily, plexin family of proteins. It is found on sensory, autonomic and motor neurons and oligodendrocytes, plus T cells and dendritic cells. Mature human Plexin A4 is an 1871 amino acid (aa) type I transmembrane glycoprotein with a 23aa signal sequence, a 1214aa extracellular domain (ECD), and a 636aa cytoplasmic region. The ECD contains one Sema-domain (aa51-482), three PSI domains (aa509-856) and four IPT regions (aa858-1230) that contain a phosphoserine at aa 946. Of three isoform variants, one shows a 65aa substitution for aa458-1894, a second shows an 80aa substitution for aa1292-1894, and a third shows the just mentioned 80aa substitution coupled to a 14aa substitution for aa1-535. The human Plexin A4 ECD shares 97% aa identity with mouse, equine, canine, and bovine Plexin A4. Full-length Plexin A4 also shares 67% aa identity with the most related family member, Plexin A2. Plexin A4 regulates cell migration, activation and axon guidance via repulsion. It serves as a receptor for transmembrane semaphorins, Sema6A and 6B, and as a coreceptor with neuropilin-1 for the secreted semaphorin, Sema3A. During development, it plays a role in nerve migration and midline crossing and down-regulates dendrite formation. It is often co-expressed with Plexin A3, which can also engage class 6 semaphorins but prefers Sema3F/neuropilin-2 to Sema3A/neuropilin-1. Thus, Plexins A3 and A4 are redundant in some functions, but unique in others. In T cells, Plexin A4 engages Sema3A and negatively regulates TCR signals.