Receptor binding properties of four-helix-bundle growth factors deduced from electrostatic analysis.
Hormones of the hematopoietin class mediate signal transduction by binding to specific transmembrane receptors. Structural data show that the human growth hormone (hGH) forms a complex with a homodimeric receptor and that hGH is a member of a class of hematopoietins possessing an antiparallel 4-alpha-helix bundle fold. Mutagenesis experiments suggest that electrostatic interactions may have an important influence on hormone-receptor recognition. In order to examine the specificity of hormone-receptor complexation, an analysis was made of the electrostatic potentials of hGH, interleukin-2 (IL-2), interleukin-4 (IL-4), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and the hGH and IL-4 receptors. The binding surfaces of hGH and its receptor, and of IL-4 and its receptor, show complementary electrostatic potentials. The potentials of the hGH and its receptor display approximately 2-fold rotational symmetry because the receptor subunits are identical. In contrast, the potentials of GM-CSF and IL-2 lack such symmetry, consistent with their known high affinity for hetero-oligomeric receptors. Analysis of the electrostatic potentials supports a recently proposed hetero-oligomeric model for a high-affinity IL-4 receptor and suggests a possible new receptor binding mode for G-CSF; it also provides valuable information for guiding structural and mutagenesis studies of signal-transducing proteins and their receptors.
Demchuk
E
E
European Molecular Biology Laboratory, Heidelberg, Germany.
Mueller
T
T
Oschkinat
H
H
Sebald
W
W
Wade
R C
RC
D004563:Electrochemistry; D016179:Granulocyte Colony-Stimulating Factor / Q000737:chemistry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000737:chemistry; D013006:Growth Hormone / Q000737:chemistry / Q000378:metabolism; D006133:Growth Substances / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2; D015847:Interleukin-4; D046911:Macromolecular Substances; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D017978:Receptors, Growth Factor / Q000737:chemistry / Q000378:metabolism*; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen / Q000737:chemistry / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000737:chemistry / Q000378:metabolism
D006133:Growth Substances; D007376:Interleukin-2; D046911:Macromolecular Substances; D017978:Receptors, Growth Factor; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D011986:Receptors, Somatotropin; D016179:Granulocyte Colony-Stimulating Factor; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013006:Growth Hormone