Figure 5. Vascular endothelial growth factor A (VEGF-A)₁₆₅b and VEGF-A₁₆₅ interaction with VEGF receptor 2 (VEGFR2).

a | The VEGFR2 binding site of VEGF-A₁₆₅ interacts with the VEGFR2 extracellular domain. VEGF-A₁₆₅ functions as a dimer and promotes the formation of VEGFR2 dimers (only one receptor is shown here for clarity) resulting in activation of the split kinase domains (green lines) and the phosphorylation of tyrosine residues 951, 1152 and 1214 (orange) and 1054 (purple). The charged residues at the carboxy-terminal end of the VEGF-A₁₆₅ molecule (omitted for clarity) are required for VEGFR activation and, in receptor tyrosine kinases, this is thought to occur through torsional rotation of the intracellular domain bringing together the split kinase domains. Tyrosine 1054 is located at the mouth of the ATP binding pocket of the tyrosine kinase and, once phosphorylated, prevents the binding pocket from closing, thus resulting in a stable open structure. This results in formation of a persistently functional kinase from the split kinase domains, resulting in sustained cis- and trans- phosphorylation of the tyrosine residues on the intracellular tail, even in the presence of phosphatases. Robust tyrosine phosphorylation also results in the activation of angiogenic signalling pathways (FIG. 3). b | VEGF-A₁₆₅b binds the VEGFR2 binding site with equal affinity to VEGF-A₁₆₅ but does not bind neuropilin 1 (NRP1). The C’ terminus of VEGF-A₁₆₅b is neutral and there is insufficient torsional rotation for tyrosine 1054 to be phosphorylated, although weak phosphorylation of the other tyrosines can occur. Thus, the ATP binding pocket closes and the phosphorylated tyrosines can be rapidly dephosphorylated by phosphatases and trafficked much more quickly. As a result, angiogenic signalling pathways are not activated²⁵.