PMID: 21148085

 

    Legend: Gene, Sites

Title : Structural determinants of vascular endothelial growth factor-D receptor binding and specificity

Abstract :

1. Vascular endothelial growth factors ( VEGFs ) and their tyrosine kinase receptors ( VEGFR-1-3 ) are central mediators of angiogenesis and lymphangiogenesis
2. VEGFR-3 ligands VEGF-C and VEGF-D are produced as precursor proteins with long N- and C-terminal propeptides and show enhanced VEGFR-2 and VEGFR-3 binding on proteolytic removal of the propeptides
3. Two different proteolytic cleavage sites have been reported in the VEGF-D N-terminus
4. We report here the crystal structure of the human VEGF-D Cys117Ala mutant at 2.9 Å resolution
5. Comparison of the VEGF-D and VEGF-C structures shows similar extended N-terminal helices, conserved overall folds, and VEGFR-2 interacting residues
6. Consistent with this, the affinity and the thermodynamic parameters for VEGFR-2 binding are very similar
7. In comparison with VEGF-C structures, however, the VEGF-D N-terminal helix was extended by 2 more turns because of a better resolution
8. Both receptor binding and functional assays of N-terminally truncated VEGF-D polypeptides indicated that the residues between the reported proteolytic cleavage sites are important for VEGF-D binding and activation of VEGFR-3 , but not of VEGFR-2
9. Thus, we define here a VEGFR-2-specific form of VEGF-D that is angiogenic but not lymphangiogenic
10. These results provide important new insights into VEGF-D structure and function

Output (sent_index, trigger, protein, sugar, site):

• 0. factor-D, , vascular endothelial growth factor-D, Structural determinants, -

Output(Part-Of) (sent_index, protein, site):

• 2. proteins, propeptides
• 5. VEGFR-2, residues
• 8. VEGF-D, polypeptides

*Output_Site_Fusion* (sent_index, protein, sugar, site):

 

Protein	NCBI ID	SENTENCE INDEX
VEGFR-2	3791	2,5,6,8,9
VEGFR-3	2324	2,8
VEGFR-1-3	2321	1