Beyond dimerization: a membrane-dependent activation model for interleukin-4 receptor-mediated signalling.
Class I cytokine receptors efficiently transfer activation signals from the extracellular space to the cytoplasm and play a dominant role in growth control and differentiation of human tissues. Although a significant body of literature is devoted to this topic, a consistent mechanistic picture for receptor activation in the membrane environment is still missing. Using the interleukin-4 receptor (IL-4R) as an example, we propose that the membrane-proximal stem-loop of the extracellular domains contains pivotal elements of a rotational switch. Interfacial energies of amino acid side-chains contained in the highly conserved WSXWS at the surface of the lipid bilayer suggest a new functional role for this motif. A generic activation mechanism for this receptor class is presented, which may impact the design of a new generation of biophysical assay systems.
Weidemann
Thomas
T
Innovative Screening Technologies, Novartis Institutes for BioMedical Research, Brunnerstr 59, A-1235 Vienna, Austria. tj.weidemann@web.de
Höfinger
Siegfried
S
Müller
Kurt
K
Auer
Manfred
M
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D017124:Conserved Sequence; D019281:Dimerization; D006801:Humans; D008024:Ligands; D008051:Lipid Bilayers / Q000737:chemistry; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D019948:Receptors, Interleukin-4 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
D008024:Ligands; D008051:Lipid Bilayers; D019948:Receptors, Interleukin-4