PMID: 20145116

 

    Legend: Gene, Sites

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
Output (sent_index, trigger, protein, sugar, site):
Output(Part-Of) (sent_index, protein, site):
  • 13. VEGFR-2, residues
  • 2. VEGF receptors, domain
  • 3. receptor, domain
  • 6. VEGFR, site
  • 7. receptor, domains
  • 9. VEGFR-2, subdomains
*Output_Site_Fusion* (sent_index, protein, sugar, site):

 

 

Protein NCBI ID SENTENCE INDEX
VEGFR-1, -2, and -3 2321 1
VEGFR-2 3791 5,9,12,13
VEGFR-3 2324 4
VEGFR 3791 6,14
VEGFR-1 2321 11,12