Title

Structural Basis for VEGF-C Binding to Neuropilin-2 and Sequestration by a Soluble Splice Form

UMMS Affiliation

Department of Molecular, Cell and Cancer Biology

Date

4-7-2015

Document Type

Article

Disciplines

Biochemistry | Molecular Biology | Structural Biology

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.

Rights and Permissions

Citation: Structure. 2015 Apr 7;23(4):677-87. doi: 10.1016/j.str.2015.01.018. Epub 2015 Mar 5. Link to article on publisher's site

Related Resources

Link to Article in PubMed

PubMed ID

25752543