Beyond dimerization: a membrane-dependent activation model for interleukin-4 receptor-mediated signalling |
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Authors: | Weidemann Thomas Höfinger Siegfried Müller Kurt Auer Manfred |
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Affiliation: | Innovative Screening Technologies, Novartis Institutes for BioMedical Research, Brunnerstr 59, A-1235 Vienna, Austria. tj.weidemann@web.de |
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Abstract: | 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. |
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Keywords: | IL-4R, interleukin-4 receptor HCS, high-content screening GHR, growth hormone receptor EPOR, erythropoietin receptor TM, transmembrane FRET, fluorescence resonance energy transfer CBM, cytokine-binding module FNIII, fibronectin type III JAK, Janus kinase FEP, free energy perturbation PCM, polarizable continuum model |
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