PMID: 20145116

 

    Legend: Sugar

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

Abstract :

1. Vascular endothelial growth factors ( VEGFs ) regulate blood and lymph vessel formation through activation of three receptor tyrosine kinases, VEGFR-1, -2, and -3
2. The extracellular domain of VEGF receptors consists of seven immunoglobulin homology domains , which, upon ligand binding, promote receptor dimerization
3. Dimerization initiates transmembrane signaling, which activates the intracellular tyrosine kinase domain of the receptor
4. VEGF-C stimulates lymphangiogenesis and contributes to pathological angiogenesis via VEGFR-3
5. However, proteolytically processed VEGF-C also stimulates VEGFR-2 , the predominant transducer of signals required for physiological and pathological angiogenesis
6. Here we present the crystal structure of VEGF-C bound to the VEGFR-2 high-affinity-binding site , which consists of immunoglobulin homology domains D2 and D3
7. This structure reveals a symmetrical 22 complex, in which left-handed twisted receptor domains wrap around the 2-fold axis of VEGF-C
8. In the VEGFs , receptor specificity is determined by an N-terminal alpha helix and three peptide loops
9. Our structure shows that two of these loops in VEGF-C bind to VEGFR-2 subdomains D2 and D3, while one interacts primarily with D3
10. Additionally, the N-terminal helix of VEGF-C interacts with D2, and the groove separating the two VEGF-C monomers binds to the D2/D3 linker
11. VEGF-C, unlike VEGF-A, does not bind VEGFR-1
12. We therefore created VEGFR-1 / VEGFR-2 chimeric proteins to further study receptor specificity
13. This biochemical analysis, together with our structural data, defined VEGFR-2 residues critical for the binding of VEGF-A and VEGF-C
14. Our results provide significant insights into the structural features that determine the high affinity and specificity of VEGF / VEGFR interactions