Structural basis for VEGF-C binding to neuropilin-2 and sequestration by a soluble splice form

Matthew W. Parker, Andrew D. Linkugel, Hira Lal Goel, Tingting Wu, Arthur M. Mercurio, Craig W. Vander Kooi

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Vascular endothelial growth factor C (VEGF-C) is a potent lymphangiogenic cytokine that signals via the coordinated action of two cell surface receptors, Neuropilin-2 (Nrp2) and VEGFR-3. Diseases associated with both loss and gain of VEGF-C function, lymphedema and cancer, respectively, motivate studies of VEGF-C/Nrp2 binding and inhibition. Here, we demonstrate that VEGF-C binding to Nrp2 is regulated by C-terminal proteolytic maturation. The structure of the VEGF-C C terminus in complex with the ligand binding domains of Nrp2 demonstrates that a cryptic Nrp2 binding motif is released upon proteolysis, allowing specific engagement with the b1 domain of Nrp2. Based on the identified structural requirements for Nrp2 binding to VEGF-C, we hypothesized that the endogenous secreted splice form of Nrp2, s9Nrp2, may function as a selective inhibitor of VEGF-C. We find that s9Nrp2 forms a stable dimer that potently inhibits VEGF-C/Nrp2 binding and cellular signaling. These data provide critical insight into VEGF-C/Nrp2 binding and inhibition.

Original languageEnglish (US)
Pages (from-to)677-687
Number of pages11
JournalStructure
Volume23
Issue number4
DOIs
StatePublished - Apr 7 2015

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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