The WSXWS Motif in Cytokine Receptors Is a Molecular Switch Involved in Receptor Activation: Insight from Structures of the Prolactin Receptor
The WSXWS Motif in Cytokine Receptors Is a Molecular Switch Involved in Receptor Activation: Insight from Structures of the Prolactin Receptor
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DOI：
10.1016/j.str.2011.12.010
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发表时间：
2012-02-08
期刊：
影响因子：
5.7
通讯作者：
Kragelund, Birthe B.
中科院分区：
文献类型：
--
作者：
Dagil, Robert;Knudsen, Maiken J.;Kragelund, Birthe B.
催乳素受体（PRLR）通过与催乳素结合形成2：1复合物而被激活，但其激活机制尚不清楚。PRLR具有细胞因子I类受体的保守WSXWS基序。我们已经确定了核磁共振溶液结构的膜近端域的人催乳素受体，并发现该基序的双链体在未结合状态下采用T-堆叠构象。相比之下，在激素结合状态下，形成Trp/Arg-阶梯。构象的变化是依赖性的，并影响受体-受体二聚化位点3。在组成型活性，乳腺癌相关受体突变体PRLRI 146 L，我们观察到的二聚体状态的稳定和动力学的主题的变化。在这里，我们证明了WSXWS基序，激素结合，受体二聚化之间的结构联系，并提出它作为1类受体激活的一般机制。
The prolactin receptor (PRLR) is activated by binding of prolactin in a 2:1 complex, but the activation mechanism is poorly understood. PRLR has a conserved WSXWS motif generic to cytokine class I receptors. We have determined the nuclear magnetic resonance solution structure of the membrane proximal domain of the human PRLR and find that the tryptophans of the motif adopt a T-stack conformation in the unbound state. By contrast, in the hormone bound state, a Trp/Arg-ladder is formed. The conformational change is hormone-dependent and influences the receptor-receptor dimerization site 3. In the constitutively active, breast cancer-related receptor mutant PRLRI146L, we observed a stabilization of the dimeric state and a change in the dynamics of the motif. Here we demonstrate a structural link between the WSXWS motif, hormone binding, and receptor dimerization and propose it as a general mechanism for class 1 receptor activation.