Mechanisms of VEGFR2 activation by VEGF, neuropilin, and heparin
2026-07-15
Vascular endothelial growth factor (VEGF) and its receptor VEGFR are master regulators of vasculogenesis and angiogenesis. VEGF activates VEGFR by inducing its dimerization and trans-autophosphorylation. The coreceptor neuropilin (Nrp1 and Nrp2) and heparan sulfate proteoglycan (HSPG) modulate VEGF-VEGFR signaling, but the underlying mechanisms remain incompletely understood. Here we report a cryo-EM structure of the dimeric mouse VEGF 164 -VEGFR2-Nrp1 ectodomain complex with a 2:2:2 stoichiometry, revealing direct Nrp1-VEGFR2 interactions that stabilize the VEGFR2 dimer. We also determined two cryo-EM structures of the VEGF 164 -VEGFR2-Nrp1 complex in the presence of short- or long-chain heparin, which bridges all three proteins and promotes the formation of two distinct tetrameric complexes. Long-chain heparin induces a cis tetrameric complex consistent with receptor clustering on the same cell surface, whereas short-chain heparin promotes a trans tetrameric assembly which might be formed by two dimeric complexes from opposing cells. Our structure-based mutational analyses support the model that both the Nrp1-VEGFR2 interface and the heparin-mediated clustering enhance VEGFR2 signaling.