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

Proceedings of the National Academy of Sciences - PNAS, 2010-02, Vol.107 (6), p.2425-2430 [Peer Reviewed Journal]

Copyright National Academy of Sciences Feb 9, 2010 ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.0914318107 ;PMID: 20145116

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Title:
Structural determinants of growth factor binding and specificity by VEGF receptor 2
Author: Leppänen, Veli-Matti ; Prota, Andrea E ; Jeltsch, Michael ; Anisimov, Andrey ; Kalkkinen, Nisse ; Strandin, Tomas ; Lankinen, Hilkka ; Goldman, Adrian ; Ballmer-Hofer, Kurt ; Alitalo, Kari
Subjects: Angiogenesis ; Animals ; Binding sites ; Binding Sites - genetics ; Biochemistry ; Biological Sciences ; Cell Line ; Cell Survival ; Chimeras ; Crystal structure ; Crystallography, X-Ray ; Dimers ; Endothelial growth factors ; Humans ; Hydrogen Bonding ; Immunoglobulins ; Kinases ; Kinetics ; Ligands ; Membranes ; Models, Molecular ; Monomers ; Mutation ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary ; Proteins ; Receptors ; Recombinant Fusion Proteins - chemistry ; Recombinant Fusion Proteins - genetics ; Recombinant Fusion Proteins - metabolism ; Signal transduction ; Spodoptera ; Vascular Endothelial Growth Factor A - chemistry ; Vascular Endothelial Growth Factor A - genetics ; Vascular Endothelial Growth Factor A - metabolism ; Vascular Endothelial Growth Factor C - chemistry ; Vascular Endothelial Growth Factor C - genetics ; Vascular Endothelial Growth Factor C - metabolism ; Vascular Endothelial Growth Factor Receptor-1 - chemistry ; Vascular Endothelial Growth Factor Receptor-1 - genetics ; Vascular Endothelial Growth Factor Receptor-1 - metabolism ; Vascular Endothelial Growth Factor Receptor-2 - chemistry ; Vascular Endothelial Growth Factor Receptor-2 - genetics ; Vascular Endothelial Growth Factor Receptor-2 - metabolism ; Vascular Endothelial Growth Factor Receptor-3 - chemistry ; Vascular Endothelial Growth Factor Receptor-3 - genetics ; Vascular Endothelial Growth Factor Receptor-3 - metabolism ; Vascular endothelial growth factors
Is Part Of: Proceedings of the National Academy of Sciences - PNAS, 2010-02, Vol.107 (6), p.2425-2430
Description: Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel formation through activation of three receptor tyrosine kinases, VEGFR-1, -2, and -3. The extracellular domain of VEGF receptors consists of seven immunoglobulin homology domains, which, upon ligand binding, promote receptor dimerization. Dimerization initiates transmembrane signaling, which activates the intracellular tyrosine kinase domain of the receptor. VEGF-C stimulates lymphangiogenesis and contributes to pathological angiogenesis via VEGFR-3. However, proteolytically processed VEGF-C also stimulates VEGFR-2, the predominant transducer of signals required for physiological and pathological angiogenesis. 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. This structure reveals a symmetrical 2:2 complex, in which left-handed twisted receptor domains wrap around the 2-fold axis of VEGF-C. In the VEGFs, receptor specificity is determined by an N-terminal alpha helix and three peptide loops. 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. 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. VEGF-C, unlike VEGF-A, does not bind VEGFR-1. We therefore created VEGFR-1/VEGFR-2 chimeric proteins to further study receptor specificity. This biochemical analysis, together with our structural data, defined VEGFR-2 residues critical for the binding of VEGF-A and VEGF-C. Our results provide significant insights into the structural features that determine the high affinity and specificity of VEGF/VEGFR interactions.
Publisher: United States: National Academy of Sciences
Language: English
Identifier: ISSN: 0027-8424
EISSN: 1091-6490
DOI: 10.1073/pnas.0914318107
PMID: 20145116
Source: Geneva Foundation Free Medical Journals at publisher websites
MEDLINE
PubMed Central

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

Copyright National Academy of Sciences Feb 9, 2010 ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.0914318107 ;PMID: 20145116

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