02103nas a2200241   4500008004100000245010100041210006900142260001400211300001400225490000800239520135400247100002601601700002101627700002101648700002001669700001501689700002101704700001901725700002601744700002401770700001801794856004901812       2011                        eng d00aStructural determinants of vascular endothelial growth factor-D receptor binding and specificity0 aStructural determinants of vascular endothelial growth factorD r  c2011/Feb/  a1507 - 150 v1173 aVascular endothelial growth factors (VEGFs) and their tyrosine kinase receptors (VEGFR-1-3) are central mediators of angiogenesis and lymphangiogenesis. 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. Two different proteolytic cleavage sites have been reported in the VEGF-D N-terminus. We report here the crystal structure of the human VEGF-D Cys117Ala mutant at 2.9 Å resolution. Comparison of the VEGF-D and VEGF-C structures shows similar extended N-terminal helices, conserved overall folds, and VEGFR-2 interacting residues. Consistent with this, the affinity and the thermodynamic parameters for VEGFR-2 binding are very similar. In comparison with VEGF-C structures, however, the VEGF-D N-terminal helix was extended by 2 more turns because of a better resolution. 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. Thus, we define here a VEGFR-2-specific form of VEGF-D that is angiogenic but not lymphangiogenic. These results provide important new insights into VEGF-D structure and function.1 aLeppänen, Veli-Matti1 aJeltsch, Michael1 aAnisimov, Andrey1 aTvorogov, Denis1 aAho, Kukka1 aKalkkinen, Nisse1 aToivanen, Pyry1 aYlä-Herttuala, Seppo1 aBallmer-Hofer, Kurt1 aAlitalo, Kari  uhttp://view.ncbi.nlm.nih.gov/pubmed/2114808501519nas a2200193   4500008004100000245014600041210006900187260001400256300001500270490000800285520086800293100002101161700002001182700002001202700001501222700002101237700001801258856004901276       2006                        eng d00aVascular endothelial growth factor (VEGF)/VEGF-C mosaic molecules reveal specificity determinants and feature novel receptor binding patterns0 aVascular endothelial growth factor VEGFVEGFC mosaic molecules re  c2006/Apr/  a12187 - 950 v2813 aVascular endothelial growth factors (VEGFs) and their receptors play key roles in angiogenesis and lymphangiogenesis. VEGF activates VEGF receptor-1 (VEGFR-1) and VEGFR-2, whereas VEGF-C activates VEGFR-2 and VEGFR-3. We have created a library of VEGF/VEGF-C mosaic molecules that contains factors with novel receptor binding profiles, notably proteins binding to all three VEGF receptors ("super-VEGFs"). The analyzed super-VEGFs show both angiogenic and lymphangiogenic effects in vivo, although weaker than the parental molecules. The composition of the VEGFR-3 binding molecules and scanning mutagenesis revealed determinants of receptor binding and specificity. VEGFR-2 and VEGFR-3 showed striking differences in their requirements for VEGF-C binding; extracellular domain 2 of VEGFR-2 was sufficient, whereas in VEGFR-3, both domains 1 and 2 were necessary.1 aJeltsch, Michael1 aKarpanen, Terhi1 aStrandin, Tomas1 aAho, Kukka1 aLankinen, Hilkka1 aAlitalo, Kari  uhttp://view.ncbi.nlm.nih.gov/pubmed/16505489