Abstract
Vascular endothelial growth factor (VEGF) is a homodimeric hormone that induces proliferation of endothelial cells through binding to the kinase domain receptor and the Fms-like tyrosine kinase receptor (Flt-1), the extracellular portions of which consist of seven immunoglobulin domains. We show that the second and third domains of Flt-1 are necessary and sufficient for binding VEGF with near-native affinity, and that domain 2 alone binds only 60-fold less tightly than wild-type. The crystal structure of the complex between VEGF and the second domain of Flt-1 shows domain 2 in a predominantly hydrophobic interaction with the "poles" of the VEGF dimer. Based on this structure and on mutational data, we present a model of VEGF bound to the first four domains of Flt-1.
MeSH terms
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Cells, Cultured
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Crystallography
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Endothelial Growth Factors / chemistry*
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Endothelial Growth Factors / genetics*
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Endothelial Growth Factors / metabolism
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Lymphokines / chemistry*
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Lymphokines / genetics*
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Lymphokines / metabolism
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Molecular Sequence Data
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Mutagenesis
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Peptide Fragments / metabolism
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Protein Binding
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / chemistry*
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Proto-Oncogene Proteins / metabolism
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Receptor Protein-Tyrosine Kinases / chemistry*
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptors, Platelet-Derived Growth Factor / genetics
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Sequence Homology, Amino Acid
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factors
Substances
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Endothelial Growth Factors
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Lymphokines
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Peptide Fragments
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Proto-Oncogene Proteins
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Receptor Protein-Tyrosine Kinases
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Receptors, Platelet-Derived Growth Factor
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Vascular Endothelial Growth Factor Receptor-1