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TitleMechanisms of VEGFR2 activation by VEGF, neuropilin, and heparin.
Journal, issue, pagesSci Adv, Vol. 12, Issue 29, Page eaeg6323, Year 2026
Publish dateJul 17, 2026
AuthorsLianqi Chen / Zhichen Sun / Jian Qiao / Xiao-Chen Bai / Xuewu Zhang /
PubMed AbstractVascular endothelial growth factor (VEGF) and its receptor VEGFR are master regulators of vasculogenesis and angiogenesis. VEGF activates VEGFR by inducing its dimerization and trans- ...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-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-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.
External linksSci Adv / PubMed:42455955 / PubMed Central
MethodsEM (single particle)
Resolution3.34 - 3.65 Å
Structure data

75407

10ri

EMDB-75407, PDB-10ri:
Dimeric complex of VEGF, VEGFR2 and Neuropilin 1
Method: EM (single particle) / Resolution: 3.6 Å

75408

10rj

EMDB-75408, PDB-10rj:
Heparin-induced cis tetrameric complex of VEGF, VEGFR2 and Neuropilin 1
Method: EM (single particle) / Resolution: 3.34 Å

75409

10rk

EMDB-75409, PDB-10rk:
Heparin-induced trans tetrameric complex of VEGF, VEGFR2 and Neuropilin 1
Method: EM (single particle) / Resolution: 3.65 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-CA:
Unknown entry

Source
  • mus musculus (house mouse)
KeywordsSIGNALING PROTEIN / VEGF / VEGFR / neuropilin / heparin

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