4QDQ

Physical basis for Nrp2 ligand binding

Summary for 4QDQ

• Entry DOI: 10.2210/pdb4qdq/pdb
• Related: 4QDR 4QDS
• Descriptor: Neuropilin-2, GLYCEROL, SULFATE ION, ... (4 entities in total)
• Functional Keywords: coagulation factor domain, discoidin domain, receptor, vegf-c, membrane, cell adhesion
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein. Isoform s9: Secreted : O60462
• Total number of polymer chains: 2
• Total formula weight: 74902.32

Authors

Parker, M.W.,Vander Kooi, C.W. (deposition date: 2014-05-14, release date: 2015-04-15, Last modification date: 2023-09-20)

Primary citation

Parker, M.W.,Linkugel, A.D.,Goel, H.L.,Wu, T.,Mercurio, A.M.,Vander Kooi, C.W.
Structural Basis for VEGF-C Binding to Neuropilin-2 and Sequestration by a Soluble Splice Form.
Structure, 23:677-687, 2015

PubMed 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.

PubMed: 25752543
DOI: 10.1016/j.str.2015.01.018

Experimental method

X-RAY DIFFRACTION (1.95 Å)