RECEPTOR-BINDING PROPERTIES OF 4-HELIX-BUNDLE GROWTH-FACTORS DEDUCED FROM ELECTROSTATIC ANALYSIS

Hormones of the hematopoietin class mediate signal transduction by bin ding to specific transmembrane receptors. Structural data show that th e human growth hormone (hGH) forms a complex with a homodimeric recept or and that hGH is a member of a class of hematopoietins possessing an antiparallel 4-alpha-helix bundle fold. Mutagenesis experiments sugge st that electrostatic interactions may have an important influence on hormone-receptor recognition. In order to examine the specificity of h ormone-receptor complexation, an analysis was made of the electrostati c potentials of hGH, interleukin-2 (IL-2), interleukin-4 (IL-4), granu locyte colony-stimulating factor (G-CSF), granulocyte-macrophage colon y-stimulating factor (GM-CSF), and the hGH and IL-4 receptors. The bin ding surfaces of hGH and its receptor, and of IL-4 and its receptor, s how complementary electrostatic potentials. The potentials of the hCH and its receptor display approximately 2-fold rotational symmetry beca use the receptor subunits are identical. In contrast, the potentials o f GM-CSF and IL-2 lack such symmetry, consistent with their known high affinity for hetero-oligomeric receptors. Analysis of the electrostat ic potentials supports a recently proposed hetero-oligomeric model for a high-affinity IL-4 receptor and suggests a possible new receptor bi nding mode for G-CSF; it also provides valuable information for guidin g structural and mutagenesis studies of signal-transducing proteins an d their receptors.