Angiogenesis, the formation of new blood vessels from pre-existing ones, is critical not only during normal development and wound repair but also for the growth and malignancy of solid tumors. This process is regulated by the balance of pro- and anti-angiogenic cytokines, which is exemplified by the Vascular Endothelial Growth Factor (VEGF) and Semaphorin 3 (sema3) families. Indeed, VEGF is a potent endogenous pro-angiogenesis cytokine while sema3 is a potent angiogenesis inhibitor. Interestingly, these two ligands compete for binding to the same receptor Neuropilin 1 (Nrp1). Although the importance of the competition between VEGF and sema3 for Nrp1 is well recognized, the mechanism of the interaction between sema3 and Nrp1 is not well studied. We have identified a C-terminal peptide from Sema3F that is a potent Nrp1 inhibitor both in vitro and in situ. This inhibitor has a two order of magnitude greater potency than previously reported Nrp1 inhibitors. We have determined that this unique potency is due to unique engagement of Nrp1 by Sema3F via two distinct binding sites: a C-terminal arginine binding motif and an N-terminal helical binding motif. Covalent tethering of these two motifs leads to synergistic binding to Nrp, and thus its potent anti-angiogenic activity. Interestingly the helical motif is conserved in all Sema3 family members, suggesting this tethering mode is generally utilized in Sema3.  These data provide mechanistic insight regarding Nrp1 ligand binding and also a novel mechanism for potent Nrp1 inhibition. Supported by NIH Grant GM094155.

Divalent synergistic binding of Semaphorin 3 C-terminal basic domain to Neuropilin-1 mediates its anti-angiogenic activity

246th National Meeting (2013)

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