IL-6 type cytokine receptor complexes: hexamer, tetramer or both?
The typical protein fold of most cytokines is a bundle of four antiparallel helices. This 'four-helical bundle fold' seems to be unique to cytokines and has not been detected in other proteins. Cytokine receptors, however, can be classified as a subfamily of the immunoglobulin superfamily. Cytokines using the same receptor subunits are grouped into cytokine families. The interleukin-6 (IL-6) type cytokine family comprises six members. IL-6 type cytokines may interact with three receptor subunits instead of the usual two subunits. A tetramer would be the simplest model to describe such a receptor complex, but present orthodoxy describes the active complexes of IL-6 and ciliary neurotrophic factor (CNTF) as hexamers. Here, we summarize the structural and biochemical information on IL-6 type cytokines and discuss interactions between cytokine and individual receptor subunits at alternative positions. Contradictory results regarding the stoichiometry and assembly of signaling receptor complexes are rationalized by a new, unique model. The model stipulates that a ligand-induced transition from an active tetrameric to an inactive hexameric complex serves as a molecular switch that turns off cytokine signals in the presence of supraoptimal cytokine concentrations.
Grötzinger
J
J
Institut für Biochemie, Universitätsklinikum RWTH Aachen, Germany.
Kernebeck
T
T
Kallen
K J
KJ
Rose-John
S
S
D001704:Biopolymers; D020934:Ciliary Neurotrophic Factor; D005353:Fibronectins / Q000737:chemistry; D015850:Interleukin-6 / Q000378:metabolism*; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000737:chemistry / Q000378:metabolism*
D001704:Biopolymers; D020934:Ciliary Neurotrophic Factor; D005353:Fibronectins; D015850:Interleukin-6; D009419:Nerve Tissue Proteins; D018121:Receptors, Cytokine