Neuropilin-2 is a receptor for semaphorin IV: insight into the structural basis of receptor function and specificity.
Neuropilins bind secreted members of the semaphorin family of proteins. Neuropilin-1 is a receptor for Sema III. Here, we show that neuropilin-2 is a receptor for the secreted semaphorin Sema IV and acts selectively to mediate repulsive guidance events in discrete populations of neurons. neuropilin-2 and semaIV are expressed in strikingly complementary patterns during neurodevelopment. The extracellular complement-binding (CUB) and coagulation factor domains of neuropilin-2 confer specificity to the Sema IV repulsive response, and these domains of neuropilin-1 are necessary and sufficient for binding of the Sema III semaphorin (sema) domain. The coagulation factor domains alone are necessary and sufficient for binding of the Sema III immunoglobulin- (Ig-) basic domain and the unrelated ligand, vascular endothelial growth factor (VEGF). Lastly, neuropilin-1 can homomultimerize and form heteromultimers with neuropilin-2. These results provide insight into how interactions between neuropilins and secreted semaphorins function to coordinate repulsive axon guidance during neurodevelopment.
Giger
R J
RJ
Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2185, USA.
Urquhart
E R
ER
Gillespie
S K
SK
Levengood
D V
DV
Ginty
D D
DD
Kolodkin
A L
AL
D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D004622:Embryo, Mammalian; D005727:Ganglia, Spinal / Q000166:cytology; D005728:Ganglia, Sympathetic / Q000166:cytology; D006023:Glycoproteins / Q000502:physiology; D006801:Humans; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D039942:Neuropilin-1; D051381:Rats; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000502:physiology*; D040121:Semaphorin-3A; D017783:Superior Cervical Ganglion / Q000737:chemistry / Q000166:cytology
D006023:Glycoproteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D040121:Semaphorin-3A; C099436:semaphorin IV; D039942:Neuropilin-1