Structural basis for the regulation of insulin-like growth factors by IGF binding proteins.
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.
Siwanowicz
Igor
I
Max Planck Institut für Biochemie, D-82152 Martinsried, Germany.
Popowicz
Grzegorz M
GM
Wisniewska
Magdalena
M
Huber
Robert
R
Kuenkele
Klaus-Peter
KP
Lang
Kurt
K
Engh
Richard A
RA
Holak
Tad A
TA
D000595:Amino Acid Sequence; D001665:Binding Sites; D002151:Calorimetry; D018360:Crystallography, X-Ray; D006801:Humans; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018969:Insulin-Like Growth Factor Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D018974:Insulin-Like Growth Factor Binding Protein 4; D018975:Insulin-Like Growth Factor Binding Protein 5; D018969:Insulin-Like Growth Factor Binding Proteins; D010446:Peptide Fragments; D017526:Receptor, IGF Type 1