Abstract
Insulin-like growth factor binding proteins (IGFBPs) control the extracellular distribution, function, and activity of IGFs. Here, we report an X-ray structure of the binary complex of IGF-I and the N-terminal domain of IGFBP-4 (NBP-4, residues 3-82) and a model of the ternary complex of IGF-I, NBP-4, and the C-terminal domain (CBP-4, residues 151-232) derived from diffraction data with weak definition of the C-terminal domain. These structures show how the IGFBPs regulate IGF signaling. Key features of the structures include (1) a disulphide bond ladder that binds to IGF and partially masks the IGF residues responsible for type 1 IGF receptor (IGF-IR) binding, (2) the high-affinity IGF-I interaction site formed by residues 39-82 in a globular fold, and (3) CBP-4 interactions. Although CBP-4 does not bind individually to either IGF-I or NBP-4, in the ternary complex, CBP-4 contacts both and also blocks the IGF-IR binding region of IGF-I.
MeSH terms
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Amino Acid Sequence
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Binding Sites
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Calorimetry
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Crystallography, X-Ray
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Humans
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Insulin-Like Growth Factor Binding Protein 4 / chemistry*
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Insulin-Like Growth Factor Binding Protein 4 / genetics
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Insulin-Like Growth Factor Binding Protein 4 / metabolism
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Insulin-Like Growth Factor Binding Protein 5 / chemistry*
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Insulin-Like Growth Factor Binding Protein 5 / genetics
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Insulin-Like Growth Factor Binding Protein 5 / metabolism
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Insulin-Like Growth Factor Binding Proteins / chemistry*
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Insulin-Like Growth Factor Binding Proteins / metabolism
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Kinetics
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Models, Molecular
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Molecular Sequence Data
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Mutagenesis, Site-Directed
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Nuclear Magnetic Resonance, Biomolecular
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Peptide Fragments / metabolism
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Phosphorylation
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Protein Binding
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Protein Structure, Tertiary
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Receptor, IGF Type 1 / metabolism
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Sequence Homology, Amino Acid
Substances
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Insulin-Like Growth Factor Binding Protein 4
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Insulin-Like Growth Factor Binding Protein 5
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Insulin-Like Growth Factor Binding Proteins
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Peptide Fragments
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Receptor, IGF Type 1