title: Receptor binding properties of four-helix-bundle growth factors deduced from electrostatic analysis.
abstract: 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.
authors.affiliation: European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Demchuk
authors.forename: T
authors.initials: T
authors.lastname: Mueller
authors.forename: H
authors.initials: H
authors.lastname: Oschkinat
authors.forename: W
authors.initials: W
authors.lastname: Sebald
authors.forename: R C
authors.initials: RC
authors.lastname: Wade
mesh_terms: 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
chemical_list: 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