Circadian rhythms exist in nearly all organisms. In mammals, transcriptional and translational feedback loops (TTFLs) are believed to underlie the mechanism of the circadian clock. Casein kinase 1δ/ε (CK1δ/ε) are key kinases that phosphorylate clock components such as PER proteins, determining the pace of the clock. Most previous studies of the biochemical properties of the key kinases CK1ε and CK1δ in vitro have focused on the properties of the catalytic domains from which the autoinhibitory C-terminus has been deleted (ΔC); those studies ignored the significance of self-inhibition by autophosphorylation. By comparing the properties of the catalytic domain of CK1δ/ε with the full-length kinase that can undergo autoinhibition, we found that recombinant full-length CK1 showed a sequential autophosphorylation process that induces conformational changes to affect the overall kinase activity. Furthermore, a direct relationship between the period change and the autokinase activity among CK1δ, CK1ε, and CK1ε-R178C was observed. These data implicate the autophosphorylation activity of CK1δ and CK1ε kinases in setting the pace of mammalian circadian rhythms and indicate that the circadian period can be modulated by tuning the autophosphorylation rates of CK1δ/ε.

中文翻译：

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酪蛋白激酶1δ/ε的自身激酶活性决定着哺乳动物昼夜节律的周期。

几乎所有生物体都有昼夜节律。在哺乳动物中，转录和翻译反馈环（TTFL）被认为是昼夜节律机制的基础。酪蛋白激酶1δ/ε（CK1δ/ε）是关键的激酶，可磷酸化时钟成分（例如PER蛋白），从而决定时钟的节奏。先前有关关键激酶CK1ε和CK1δ的生化特性的大多数先前研究都集中在已删除自抑制性C末端（ΔC）的催化域的特性上。这些研究忽略了通过自磷酸化进行自我抑制的重要性。通过比较CK1δ/ε催化结构域与可以进行自抑制的全长激酶的特性，我们发现重组全长CK1显示了顺序的自磷酸化过程，该过程诱导构象变化影响整体激酶活性。此外，观察到CK1δ，CK1ε和CK1ε-R178C之间的周期变化与自身激酶活性之间存在直接关系。这些数据暗示了CK1δ和CK1ε激酶的自磷酸化活性决定了哺乳动物昼夜节律的节奏，并表明可以通过调节CK1δ/ε的自磷酸化率来调节昼夜节律。