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首页> 外文期刊>Cellular Physiology and Biochemistry >Inhibition of Protein Kinase CK2 Closes the CFTR Cl- Channel, but has no Effect on the Cystic Fibrosis Mutant Delta F508-CFTR
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Inhibition of Protein Kinase CK2 Closes the CFTR Cl- Channel, but has no Effect on the Cystic Fibrosis Mutant Delta F508-CFTR

机译：抑制蛋白激酶CK2会关闭CFTR Cl-通道，但对囊性纤维化突变体Delta F508-CFTR没有影响

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Background: Deletion of phenylalanine-508 (Delta F508) from the first nucleotide-binding domain (NBD1) in the wild-type cystic fibrosis (CF) transmembrane-conductance regulator (wtCFTR) causes CF. However, the mechanistic relationship between Delta F508-CFTR and the diversity of CF disease is unexplained. The surface location of F508 on NBD1 creates the potential for protein-protein interactions and nearby, lies a consensus sequence (SYDE) reported to control the pleiotropic protein kinase CK2. Methods: Electrophysiology, immunofluorescence and biochemistry applied to CFTR-expressing cells, Xenopus oocytes, pancreatic ducts and patient biopsies. Results: Irrespective of PKA activation, CK2 inhibition (ducts, oocytes, cells) attenuates CFTR-dependent Cl- transport, closing wtCFTR in cellattached membrane patches. CK2 and wtCFTR coprecipitate and CK2 co-localized with wtCFTR (but not Delta F508-CFTR) in apical membranes of human airway biopsies. Comparing wild-type and Delta F508-CFTR expressing oocytes, only Delta F508-CFTR Cl- currents were insensitive to two CK2 inhibitors. Furthermore, wtCFTR was inhibited by injecting a peptide mimicking the F508 region, whereas the Delta F508-equivalent peptide had no effect. Conclusions: CK2 controls wtCFTR, but not Delta F508-CFTR. Others find that peptides from the F508 region of NBD1 allosterically control CK2, acting through F508. Hence, disruption of CK2-CFTR interaction by Delta F508-CFTR might disrupt multiple, membrane-associated, CK2-dependent pathways, creating a new molecular disease paradigm for deleted F508 in CFTR.
机译：背景：从野生型囊性纤维化（CF）跨膜电导调节剂（wtCFTR）的第一个核苷酸结合域（NBD1）中删除苯丙氨酸508（ΔF508）会导致CF。然而，Delta F508-CFTR与CF疾病多样性之间的机制关系尚无法解释。 NBD1上F508的表面位置产生了蛋白质与蛋白质相互作用的可能性，并且附近存在一个据报道控制多效性蛋白激酶CK2的共有序列（SYDE）。方法：将电生理，免疫荧光和生物化学应用于表达CFTR的细胞，非洲爪蟾卵母细胞，胰管和患者活检。结果：不管PKA激活如何，CK2抑制（导管，卵母细胞，细胞）都会减弱CFTR依赖的Cl-转运，从而关闭细胞贴膜补丁中的wtCFTR。 CK2和wtCFTR在人气道活检组织的顶端膜中共沉淀，而CK2与wtCFTR（但不是Delta F508-CFTR）共定位。比较野生型和表达Delta F508-CFTR的卵母细胞，只有Delta F508-CFTR C1电流对两种CK2抑制剂不敏感。此外，通过注射模拟F508区的肽可抑制wtCFTR，而Delta F508等效肽则无作用。结论：CK2控制wtCFTR，但不控制Delta F508-CFTR。其他人发现来自NBD1 F508区的肽通过F508变构地控制CK2。因此，Delta F508-CFTR破坏CK2-CFTR相互作用可能会破坏多个与膜相关的CK2依赖性途径，从而为CFTR中缺失的F508创建新的分子疾病范例。

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