Structural highlights
Function
[NRP2_HUMAN] High affinity receptor for semaphorins 3C, 3F, VEGF-165 and VEGF-145 isoforms of VEGF, and the PLGF-2 isoform of PGF.
Publication Abstract from PubMed
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.
Structural Basis for VEGF-C Binding to Neuropilin-2 and Sequestration by a Soluble Splice Form.,Parker MW, Linkugel AD, Goel HL, Wu T, Mercurio AM, Vander Kooi CW Structure. 2015 Apr 7;23(4):677-87. doi: 10.1016/j.str.2015.01.018. Epub 2015 Mar, 5. PMID:25752543[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Parker MW, Linkugel AD, Goel HL, Wu T, Mercurio AM, Vander Kooi CW. Structural Basis for VEGF-C Binding to Neuropilin-2 and Sequestration by a Soluble Splice Form. Structure. 2015 Apr 7;23(4):677-87. doi: 10.1016/j.str.2015.01.018. Epub 2015 Mar, 5. PMID:25752543 doi:http://dx.doi.org/10.1016/j.str.2015.01.018
