Structural changes of CFTR R region upon phosphorylation: a plastic platform for intramolecular and intermolecular interactions.
Structural changes of CFTR R region upon phosphorylation: a plastic platform for intramolecular and intermolecular interactions.
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DOI：
10.1111/febs.12422
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发表时间：
2013-09
期刊：
影响因子：
--
通讯作者：
Forman-Kay JD
中科院分区：
文献类型：
--
作者：
Bozoky Z;Krzeminski M;Chong PA;Forman-Kay JD
囊性纤维化跨膜电导调节因子 (CFTR) 的氯离子通道门控和运输受磷酸化调节。蛋白质本质上无序的片段负责磷酸化调节，特别是调节 (R) 区域，它是多种激酶和磷酸酶的靶点。磷酸化后，R 区保持无序状态，不同的磷酸化状态呈现不同的构象。最近的研究表明，R 区的分子内和分子间相互作用在 CFTR 调节中发挥着至关重要的作用。不同的伙伴竞争相同的结合片段，其中 R 区包含多个重叠的结合元件。非磷酸化的 R 区与核苷酸结合域相互作用，并通过阻断异二聚化来抑制通道活性。磷酸化改变了平衡，使 R 区被排除在二聚体界面之外，通过刺激 R 区与其他结构域和蛋白质的相互作用来促进门控和加工。 R 区与多个伙伴的动态构象采样和瞬时结合能够对 CFTR 通道活动和运输进行复杂的控制。
Chloride channel gating and trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) are regulated by phosphorylation. Intrinsically disordered segments of the protein are responsible for phospho‐regulation, particularly the regulatory (R) region that is a target for several kinases and phosphatases. The R region remains disordered following phosphorylation, with different phosphorylation states sampling various conformations. Recent studies have demonstrated the crucial role that intramolecular and intermolecular interactions of the R region play in CFTR regulation. Different partners compete for the same binding segment, with the R region containing multiple overlapping binding elements. The non‐phosphorylated R region interacts with the nucleotide binding domains and inhibits channel activity by blocking heterodimerization. Phosphorylation shifts the equilibrium such that the R region is excluded from the dimer interface, facilitating gating and processing by stimulating R region interactions with other domains and proteins. The dynamic conformational sampling and transient binding of the R region to multiple partners enables complex control of CFTR channel activity and trafficking.
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