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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The first armadillo repeat is involved in the recognition and regulation of β-catenin phosphorylation by protein kinase CK1
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The first armadillo repeat is involved in the recognition and regulation of β-catenin phosphorylation by protein kinase CK1

机译：第一个犰狳重复序列参与蛋白激酶CK1识别和调节β-catenin磷酸化

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摘要

Multiple phosphorylation of β-catenin by glycogen synthase kinase 3 (GSK3) in the Wnt pathway is primed by CK1 through phosphorylation of Ser-45, which lacks a typical CK1 canonical sequence. Synthetic peptides encompassing amino acids 38-64 of β-catenin are phosphorylated by CK1 on Ser-45 with low affinity (K_m ≈1 mM), whereas intact β-catenin is phosphorylated at Ser-45 with very high affinity (K_m ≈200 nM). Peptides extended to include a putative CK1 docking motif (FXXXF) at 70-74 positions or a F74AA mutation in full-length β-catenin had no significant effect on CK1 phosphorylation efficiency. β-Catenin C-terminal deletion mutants up to residue 181 maintained their high affinity, whereas removal of the 131-181 fragment, corresponding to the first armadillo repeat, was deleterious, resulting in a 50-fold increase in K_m value. Implication of the first armadillo repeat in β-catenin targeting by CK1 is supported in that the Y142E mutation, which mimics phosphorylation of Tyr-142 by tyrosine kinases and promotes dissociation of β-catenin from α-catenin, further improves CK1 phosphorylation efficiency, lowering the K_m value to < 50 nM, approximating the physiological concentration of β-catenin. In contrast, α-catenin, which interacts with the N-terminal region of β-catenin, prevents Ser-45 phosphorylation of CK1 in a dose-dependent manner. Our data show that the integrity of the N-terminal region and the first armadillo repeat are necessary and sufficient for high-affinity phosphorylation by CK1 of Ser-45. They also suggest that β-catenin association with α-catenin and β-catenin phosphorylation by CK1 at Ser-45 are mutually exclusive.
机译：Wnt途径中糖原合酶激酶3（GSK3）对β-catenin的多重磷酸化作用是由CK1通过Ser-45的磷酸化作用引发的，而后者缺乏典型的CK1规范序列。包含β-catenin氨基酸38-64的合成肽被CK1在Ser-45上以低亲和力（K_m≈1mM）磷酸化，而完整的β-catenin在Ser-45上以非常高的亲和力（K_m≈200nM）磷酸化。 ）。肽扩展到在70-74位包括一个假定的CK1对接基序（FXXXF）或全长β-catenin中的F74AA突变，对CK1磷酸化效率没有明显影响。直至残基181的β-CateninC末端缺失突变体保持其高亲和力，而对应于第一个犰狳重复的131-181片段的去除却是有害的，导致K_m值增加了50倍。支持CK1靶向β-catenin的第一个犰狳重复序列的含义在于，Y142E突变模拟酪氨酸激酶使Tyr-142磷酸化，并促进β-catenin从α-catenin的解离，进一步提高CK1磷酸化效率，降低K_m值<50 nM，近似于β-catenin的生理浓度。相反，与β-catenin的N末端区域相互作用的α-catenin可以剂量依赖性地阻止CK1的Ser-45磷酸化。我们的数据表明，N末端区域和第一个犰狳重复序列的完整性对于通过Ser-45的CK1进行高亲和力磷酸化是必要和充分的。他们还暗示，在Ser-45处，CK1与β-catenin的结合与α-catenin和β-catenin的磷酸化相互排斥。

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