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{{STRUCTURE_4bsk|  PDB=4bsk  |  SCENE=  }}
==Crystal structure of VEGF-C in complex with VEGFR-3 domains D1-2==
===Crystal structure of VEGF-C in complex with VEGFR-3 domains D1-2===
<StructureSection load='4bsk' size='340' side='right' caption='[[4bsk]], [[Resolution|resolution]] 4.20&Aring;' scene=''>
{{ABSTRACT_PUBMED_23878260}}
== Structural highlights ==
 
<table><tr><td colspan='2'>[[4bsk]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BSK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BSK FirstGlance]. <br>
==Disease==
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4bsj|4bsj]]</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4bsk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bsk OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bsk RCSB], [http://www.ebi.ac.uk/pdbsum/4bsk PDBsum]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/VGFR3_HUMAN VGFR3_HUMAN]] Milroy disease. The disease is caused by mutations affecting the gene represented in this entry.  Disease susceptibility is associated with variations affecting the gene represented in this entry.  Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases.  
[[http://www.uniprot.org/uniprot/VGFR3_HUMAN VGFR3_HUMAN]] Milroy disease. The disease is caused by mutations affecting the gene represented in this entry.  Disease susceptibility is associated with variations affecting the gene represented in this entry.  Plays an important role in tumor lymphangiogenesis, in cancer cell survival, migration, and formation of metastases.  
== Function ==
[[http://www.uniprot.org/uniprot/VGFR3_HUMAN VGFR3_HUMAN]] Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'.<ref>PMID:8700872</ref> <ref>PMID:7675451</ref> <ref>PMID:9435229</ref> <ref>PMID:11532940</ref> <ref>PMID:15474514</ref> <ref>PMID:15102829</ref> <ref>PMID:16076871</ref> <ref>PMID:16452200</ref> <ref>PMID:17210781</ref> <ref>PMID:19779139</ref> <ref>PMID:19610651</ref> <ref>PMID:20431062</ref> <ref>PMID:20224550</ref> <ref>PMID:20445537</ref> <ref>PMID:21273538</ref>  [[http://www.uniprot.org/uniprot/VEGFC_HUMAN VEGFC_HUMAN]] Growth factor active in angiogenesis, and endothelial cell growth, stimulating their proliferation and migration and also has effects on the permeability of blood vessels. May function in angiogenesis of the venous and lymphatic vascular systems during embryogenesis, and also in the maintenance of differentiated lymphatic endothelium in adults. Binds and activates VEGFR-2 (KDR/FLK1) and VEGFR-3 (FLT4) receptors.<ref>PMID:20145116</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are key drivers of blood and lymph vessel formation in development, but also in several pathological processes. VEGF-C signaling through VEGFR-3 promotes lymphangiogenesis, which is a clinically relevant target for treating lymphatic insufficiency and for blocking tumor angiogenesis and metastasis. The extracellular domain of VEGFRs consists of seven Ig homology domains; domains 1-3 (D1-3) are responsible for ligand binding, and the membrane-proximal domains 4-7 (D4-7) are involved in structural rearrangements essential for receptor dimerization and activation. Here we analyzed the crystal structures of VEGF-C in complex with VEGFR-3 domains D1-2 and of the VEGFR-3 D4-5 homodimer. The structures revealed a conserved ligand-binding interface in D2 and a unique mechanism for VEGFR dimerization and activation, with homotypic interactions in D5. Mutation of the conserved residues mediating the D5 interaction (Thr446 and Lys516) and the D7 interaction (Arg737) compromised VEGF-C induced VEGFR-3 activation. A thermodynamic analysis of VEGFR-3 deletion mutants showed that D3, D4-5, and D6-7 all contribute to ligand binding. A structural model of the VEGF-C/VEGFR-3 D1-7 complex derived from small-angle X-ray scattering data is consistent with the homotypic interactions in D5 and D7. Taken together, our data show that ligand-dependent homotypic interactions in D5 and D7 are essential for VEGFR activation, opening promising possibilities for the design of VEGFR-specific drugs.


==Function==
Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation.,Leppanen VM, Tvorogov D, Kisko K, Prota AE, Jeltsch M, Anisimov A, Markovic-Mueller S, Stuttfeld E, Goldie KN, Ballmer-Hofer K, Alitalo K Proc Natl Acad Sci U S A. 2013 Jul 22. PMID:23878260<ref>PMID:23878260</ref>
[[http://www.uniprot.org/uniprot/VGFR3_HUMAN VGFR3_HUMAN]] Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'.<ref>PMID:8700872</ref> <ref>PMID:7675451</ref> <ref>PMID:9435229</ref> <ref>PMID:11532940</ref> <ref>PMID:15474514</ref> <ref>PMID:15102829</ref> <ref>PMID:16076871</ref> <ref>PMID:16452200</ref> <ref>PMID:17210781</ref> <ref>PMID:19779139</ref> <ref>PMID:19610651</ref> <ref>PMID:20431062</ref> <ref>PMID:20224550</ref> <ref>PMID:20445537</ref> <ref>PMID:21273538</ref>  [[http://www.uniprot.org/uniprot/VEGFC_HUMAN VEGFC_HUMAN]] Growth factor active in angiogenesis, and endothelial cell growth, stimulating their proliferation and migration and also has effects on the permeability of blood vessels. May function in angiogenesis of the venous and lymphatic vascular systems during embryogenesis, and also in the maintenance of differentiated lymphatic endothelium in adults. Binds and activates VEGFR-2 (KDR/FLK1) and VEGFR-3 (FLT4) receptors.<ref>PMID:20145116</ref>


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[4bsk]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BSK OCA].
</div>


==See Also==
==See Also==
*[[Vascular Endothelial Growth Factor|Vascular Endothelial Growth Factor]]
*[[Vascular Endothelial Growth Factor|Vascular Endothelial Growth Factor]]
 
*[[Vascular Endothelial Growth Factor Receptor|Vascular Endothelial Growth Factor Receptor]]
==Reference==
== References ==
<ref group="xtra">PMID:023878260</ref><references group="xtra"/><references/>
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Alitalo, K.]]
[[Category: Alitalo, K]]
[[Category: Anisimov, A.]]
[[Category: Anisimov, A]]
[[Category: Ballmer-Hofer, K.]]
[[Category: Ballmer-Hofer, K]]
[[Category: Goldie, K N.]]
[[Category: Goldie, K N]]
[[Category: Jeltsch, M.]]
[[Category: Jeltsch, M]]
[[Category: Kisko, K.]]
[[Category: Kisko, K]]
[[Category: Leppanen, V M.]]
[[Category: Leppanen, V M]]
[[Category: Markovic-Mueller, S.]]
[[Category: Markovic-Mueller, S]]
[[Category: Prota, A E.]]
[[Category: Prota, A E]]
[[Category: Stuttfeld, E.]]
[[Category: Stuttfeld, E]]
[[Category: Tvorogov, D.]]
[[Category: Tvorogov, D]]
[[Category: Angiogenesis]]
[[Category: Angiogenesis]]
[[Category: Dimerization]]
[[Category: Dimerization]]

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