Structural determinants of growth factor binding and specificity by VEGF receptor 2

• DOI: 10.1073/pnas.0914318107
• Publication Date: 2010-01-23T03:14:56Z
• Authors: Veli-Matti Leppänen; Andrea E. Prota; Michael Jeltsch; Andrey Anisimov; Nisse Kalkkinen; Tomas Strandin; Hilkka Lankinen; Adrian Goldman; Kurt Ballmer-Hofer; Kari Alitalo
• Keywords: Models, Molecular; Vascular Endothelial Growth Factor A; 0301 basic medicine; Binding Sites; Vascular Endothelial Growth Factor Receptor-1; Cell Survival; Protein Conformation; Recombinant Fusion Proteins; Vascular Endothelial Growth Factor C; Hydrogen Bonding; Spodoptera; Crystallography, X-Ray; Vascular Endothelial Growth Factor Receptor-3; Vascular Endothelial Growth Factor Receptor-2; Cell Line; Protein Structure, Tertiary; 3. Good health; Kinetics; 03 medical and health sciences; Mutation; Animals; Humans; Protein Binding

Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel formation through activation of three receptor tyrosine kinases, VEGFR-1, -2, -3. The extracellular domain VEGF receptors consists seven immunoglobulin homology domains, which, upon ligand binding, promote dimerization. Dimerization initiates transmembrane signaling, which activates the intracellular kinase receptor. VEGF-C stimulates lymphangiogenesis contributes to pathological angiogenesis via VEGFR-3. However, proteolytically processed also VEGFR-2, predominant transducer signals required for physiological angiogenesis. Here we present crystal structure bound VEGFR-2 high-affinity-binding site, domains D2 D3. This reveals a symmetrical 2∶2 complex, in left-handed twisted wrap around 2-fold axis VEGF-C. In VEGFs, specificity is determined by an N-terminal alpha helix peptide loops. Our shows that two these loops bind subdomains D3, while one interacts primarily with Additionally, D2, groove separating monomers binds D2/D3 linker. VEGF-C, unlike VEGF-A, does not VEGFR-1. We therefore created VEGFR-1/VEGFR-2 chimeric proteins further study specificity. biochemical analysis, together our structural data, defined residues critical binding VEGF-A results provide significant insights into features determine high affinity VEGF/VEGFR interactions.