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-a-helix bundle fold. Mutagenesis experiments suggest that electrostatic interactions may have an important influence on hormonereceptor 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.

LIF receptor‐gp130 interaction investigated by homology modeling: Implications for LIF binding

“…The importance of electrostatic interactions in helical cytokine-receptor interactions has been shown by mutagenesis studies (Lopez et al, 1992;Cunningham & Wells, 1993;Kruse et al, 1993;Zurawski et al, 1993;Clackson & Wells, 1995;Graber et al, 1995;Olins et al, 1995) and the electrostatic complementarity of GH to its receptors has also been described (Demchuk et al, 1994: Layton et al, 1997. In the case of the LIF receptor complex, the models of the second CBD of LIFR and the CBD of gp130 showed a very clear electrostatic complementarity over the region that would be expected to dimerize if the complex formed in a manner similar to that of GH-GHR (Fig.…”

“…Calculations of the electrostatic isopotential surfaces of the models followed the general principle described by Demchuk et al (1994).…”

A mixed-charge pair in human interleukin 4 dominates high-affinity interaction with the receptor α chain

“…USA 94 (1997)assumption that the large transient interfaces formed by the association of cytokines and cytokine receptors are mainly hydrophobic, similar to the interior of proteins (26). Electrostatic steering likely contributes to the fast association rate constant of 1.3 ϫ 10 7 M Ϫ1 ⅐s Ϫ1 between IL-4 and IL4-BP (29). All charged residues in the k on epitope of IL-4 as depicted in Fig.…”

“…(iii) A conspicuous feature of human IL-4 is a highly positive net charge and in particular a cluster of basic residues in helix C. This patch of positive charges has been surmised to be important for complex formation, since a surplus of negatively charged side chains is found in the modeled interface of IL4-BP. ''Electrostatic steering'' has been invoked to explain the fast association rate for IL-4͞IL4-BP complex formation (29).…”

Design of human interleukin‐4 antagonists inhibiting interleukin‐4‐dependent and interleukin‐13‐dependent responses in T‐cells and B‐cells with high efficiency

“…The signalling activity of this site depends on a hydrophobic patch provided by Tyrl24 (or another large hydrophobic side chain) and is weakened specifically if the negatively charged side chain of aspartic acid is present (Demchuk et al, 1994). The occurrence at positions 121 and 125 of small, large hydrophobic, polar, or glutamyl residues introduced at this position has no or only small effects (Kruse N. and Sebald, W., unpublished results) Accordingly, an aspartic acid residue at position 121 is more inhibitory than an aspartic acid residue at position 125.…”