Activation of transmembrane cell-surface receptors via a common mechanism? The "rotation model"

Abstract

It has long been thought that transmembrane cell-surface receptors, such as receptor tyrosine kinases and cytokine receptors, among others, are activated by ligand binding through ligand-induced dimerization of the receptors. However, there is growing evidence that prior to ligand binding, various transmembrane receptors have a preformed, yet inactive, dimeric structure on the cell surface. Various studies also demonstrate that during transmembrane signaling, ligand binding to the extracellular domain of receptor dimers induces a rotation of transmembrane domains, followed by rearrangement and/or activation of intracellular domains. The paper here describes transmembrane cell-surface receptors that are known or proposed to exist in dimeric form prior to ligand binding, and discusses how these preformed dimers are activated by ligand binding.

Keywords: cytokine; dimerization; ligand binding; preformed dimer; transmembrane signaling; tyrosine kinase.

Figure 1

“Rotation model” of transmembrane signaling mediated by cell‐surface receptors. Prior to ligand binding, receptors exist in dimeric form on the cell surface. The ICD dimer has a relatively stable structure while the ligand‐binding ECD dimer has a rotationally flexible structure. Ligand binding stabilizes the flexible ECDs and induces conformational changes of the domains. This extracellular conformational change in turn induces or allows a rotation of the TMDs, which rearranges the ICDs, making them flexible for activation and/or interaction with other cytoplasmic proteins. Rotation of TMDs occurs together with changes in interhelical crossing angles and distances.