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首页> 外文期刊>Journal of Molecular Biology >Ligand-induced assembling of the type I interferon receptor on supported lipid bilayers.
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Ligand-induced assembling of the type I interferon receptor on supported lipid bilayers.

机译：配体诱导的I型干扰素受体在支持的脂质双层上的组装。

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摘要

Type I interferons (IFNs) elicit antiviral, antiproliferative and immuno-modulatory responses through binding to a shared receptor consisting of the transmembrane proteins ifnar1 and ifnar2. Differential signaling by different interferons, in particular IFNalphas and IFNbeta, suggests different modes of receptor engagement. Using reflectometric interference spectroscopy (RIfS), we studied kinetics and affinities of the interactions between IFNs and the extracellular receptor domains of ifnar1 (ifnar1-EC) and ifnar2 (ifnar2-EC). For IFNalpha2, we determined a K(D) value of 3 nM and 5 microM for the interaction with ifnar2-EC and ifnar1-EC, respectively. As compared to IFNalpha2, IFNbeta formed complexes with ifnar2-EC as well as ifnar1-EC with substantially higher affinity. For neither IFNalpha2 nor IFNbeta was stabilization of the complex with ifnar1-EC in the presence of soluble ifnar2-EC observed. We investigated ligand-induced complex formation with ifnar1-EC and ifnar2-EC being tethered onto solid-supported, fluid lipid bilayers by RIfS and total internal reflection fluorescence spectroscopy. We observed very stable binding of IFNalpha2 at high receptor surface concentrations with an apparent k(d) value approximately 200 times lower than that for ifnar2-EC alone. The apparent k(d) value was strongly dependent on the surface concentration of the receptor components, suggesting kinetic stabilization. This was corroborated by the fast exchange of labeled IFNalpha2 bound to the receptor by unlabeled IFNalpha2. Taken together, our results indicate that IFN first binds to ifnar2 and subsequently recruits ifnar1 in a transient fashion. In particular, this second step is much more efficient for IFNbeta than for IFNalpha2, which could explain differential activities observed for these IFNs.
机译：I型干扰素（IFN）通过与由跨膜蛋白ifnar1和ifnar2组成的共享受体结合，引起抗病毒，抗增殖和免疫调节反应。不同干扰素（特别是IFNα和IFNβ）的差异信号表明受体参与的方式不同。使用反射干涉光谱法（RIfS），我们研究了IFN与ifnar1（ifnar1-EC）和ifnar2（ifnar2-EC）的细胞外受体域之间相互作用的动力学和亲和力。对于IFNalpha2，我们确定与ifnar2-EC和ifnar1-EC的相互作用的K（D）值分别为3 nM和5 microM。与IFNalpha2相比，IFNbeta与ifnar2-EC以及ifnar1-EC形成的复合物具有更高的亲和力。对于IFNalpha2和IFNbeta，在存在可溶性ifnar2-EC的情况下，均未使用ifnar1-EC稳定复合物。我们研究了配体诱导的复合物的形成，其中ifnar1-EC和ifnar2-EC通过RIfS和全内反射荧光光谱法被束缚在固体支持的液体脂质双层上。我们在高受体表面浓度下观察到了非常稳定的IFNalpha2结合，其表观k（d）值比单独使用ifnar2-EC时低约200倍。表观k（d）值在很大程度上取决于受体成分的表面浓度，表明动力学稳定。通过未标记的IFNα2与受体结合的标记的IFNα2的快速交换，证实了这一点。两者合计，我们的结果表明，IFN首先与ifnar2结合，随后以瞬时方式募集ifnar1。特别是，第二步对IFNbeta的效率比对IFNalpha2的效率要高得多，这可以解释观察到的这些IFN的差异活性。

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