A Common Model for Cytokine Receptor Activation: Combined Scissor-Like Rotation and Self-Rotation of Receptor Dimer Induced by Class I Cytokine

Abstract

The precise mechanism by which the binding of a class I cytokine to the extracellular domain of its corresponding receptor transmits a signal through the cell membrane remains unclear. Receptor activation involves a cytokine-receptor complex with a 1∶2 stoichiometry. Previously we used our transient-complex theory to calculate the rate constant of the initial cytokine-receptor binding to form a 1∶1 complex. Here we computed the binding pathway leading to the 1∶2 activation complex. Three cytokine systems (growth hormone, erythropoietin, and prolactin) were studied, and the focus was on the binding of the extracellular domain of the second receptor molecule after forming the 1∶1 complex. According to the transient-complex theory, translational and rotation diffusion of the binding entities bring them together to form a transient complex, which has near-native relative separation and orientation but not the short-range specific native interactions. Subsequently conformational rearrangement leads to the formation of the native complex. We found that the changes in relative orientations between the two receptor molecules from the transient complex to the 1∶2 native complex are similar for the three cytokine-receptor systems. We thus propose a common model for receptor activation by class I cytokines, involving combined scissor-like rotation and self-rotation of the two receptor molecules. Both types of rotations seem essential: the scissor-like rotation separates the intracellular domains of the two receptor molecules to make room for the associated Janus kinase molecules, while the self-rotation allows them to orient properly for transphosphorylation. This activation model explains a host of experimental observations. The transient-complex based approach presented here may provide a strategy for designing antagonists and prove useful for elucidating activation mechanisms of other receptors.

Type I Interferon Signaling Is Decoupled from Specific Receptor Orientation through Lenient Requirements of the Transmembrane Domain

“…Evidence for such a mechanism has been shown for EPOR, growth hormone receptor, and thrombopoietin receptor (21,22,25,52,53). For the type I interferon receptor, the situation is less clear.…”

Selection of antibodies that regulate phenotype from intracellular combinatorial antibody libraries

“…Remarkably, we selected a mechanistically unique antibody whose agonist function depends on the obligate synergy between two different antigen-binding specificities that must be contained within the same antibody molecule. This asymmetric binding of the heterodimeric antibody replicates the mechanism of authentic EPO whose full agonist activity depends on activation of the JAK2/Stat5 pathway by its asymmetric binding to two nearly identical sites on the EPO receptor (EpoR) monomers (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”

“…Thus, both EPO and the bispecific antibody achieve the obligatory asymmetric binding to the EpoR that is necessary for full agonist activity, albeit in different ways. In the case of EPO, asymmetry is achieved by the use of two distinct interfaces (site 1 and site 2) that each bind with different affinities to essentially a single site in the homodimeric EpoR (14,15,22,23,25,26) By contrast, the heterodimeric bispecific antibody achieves asymmetry by using its two different binding specificities to interact with different sites on the EpoR (Fig. 6).…”

Signals in motion: Determining how signal transduction is mechanically coupled through type-I cytokine receptors

“…Its mechanism of activation, in particular how the binding of a ligand on the extracellular domains is transmitted through the plasma membrane, has therefore been of prime interest for pharmaceutical development. A critical question in the activation of EPOR is whether differences in the relative arrangement of the soluble extracellular domains within the sEPOR dimers observed in the available crystal structures are truly indicative of the active or inactive states as has been widely assumed [5,6,7,8,22,9].…”

“…The receptor chains A and B are coloured green and blue respectively, and the cytokine is coloured red. The orange spheres represent the protein kinase domain of the JAK protein associated with the cytosolic domains of the receptor that require the correct alignment of two domains in order to transphosphorylate. been the subject of continuing debate with a number of alternative models having been proposed [16,8,20,21,22]. The main models of activation are ligand-induced dimerisation (Figure 1.3A) [16], a change in the relative orientation of the receptor chains ( Figure 1.3B) [21], and cross-action scissor-like motion of the receptor chains ( Figure 1.3C) [8,20,22].…”