CK1δ/ε protein kinase primes the PER2 circadian phosphoswitch.
CK1δ/ε protein kinase primes the PER2 circadian phosphoswitch.
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DOI：
10.1073/pnas.1721076115
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发表时间：
2018-06-05
影响因子：
11.1
通讯作者：
Virshup DM
中科院分区：
文献类型：
--
作者：
Narasimamurthy R;Hunt SR;Lu Y;Fustin JM;Okamura H;Partch CL;Forger DB;Kim JK;Virshup DM
我们与生俱来的生物钟控制着行为和生理的方方面面。轮班工作、时差反应或遗传性突变扰乱了我们的生物钟，导致代谢失调，并导致疾病，包括糖尿病和癌症。时钟控制的一个中心步骤是PERIOD 2（PER 2）蛋白的磷酸化。在这里，我们最终确定了难以捉摸的PER 2引发激酶，并发现它是众所周知的昼夜节律激酶，酪蛋白激酶1（CK 1）。令人惊讶的是，不同形式的CK 1具有不同的磷酸化PER 2引发位点的能力，增加了昼夜节律调节的复杂性。这些对PER 2磷酸化调节的见解将引起昼夜节律生物学家、计算建模者和那些寻求药理学操纵昼夜节律钟的人的广泛兴趣。PER 2蛋白的多位点磷酸化是决定哺乳动物生物钟周期的关键步骤。先前的研究得出结论，需要一种未鉴定的激酶来引发PER 2随后被酪蛋白激酶1（CK 1）磷酸化，酪蛋白激酶1是一种从藻类到人类保守的基本时钟组分。这些随后的磷酸化稳定PER 2，延迟其降解，并延长生物钟的周期。在这里，我们对小鼠PER 2（mPER 2）引发磷酸化进行了全面的生化和生物物理分析，并令人惊讶地证明了CK 1 δ/ε确实是引发激酶。我们发现，CK 1 ε和最近表征的CK 1 δ2剪接变体都比研究充分的剪接变体CK 1 δ1更有效地引发mPER 2在细胞中的下游磷酸化。虽然先前已证明PER 2的CK 1磷酸化对细胞环境的变化具有鲁棒性，但我们的昼夜节律的磷酸开关数学模型表明，CK 1羧基末端尾可以使时钟的周期对细胞信号传导敏感。这些研究暗示CK 1的极端羧基末端是昼夜节律定时的关键调节因子。
Our innate circadian clocks control myriad aspects of behavior and physiology. Disruption of our clocks by shift work, jet lag, or inherited mutation leads to metabolic dysregulation and contributes to diseases, including diabetes and cancer. A central step in clock control is phosphorylation of the PERIOD 2 (PER2) protein. Here we conclusively identify the elusive PER2 priming kinase and find it to be the well-known circadian kinase, casein kinase 1 (CK1). Surprisingly, different forms of CK1 have differing abilities to phosphorylate the PER2 priming site, adding to the complexity of circadian regulation. These insights into the phosphoregulation of PER2 will be of broad interest to circadian biologists, computational modelers, and those seeking to pharmacologically manipulate the circadian clock. Multisite phosphorylation of the PERIOD 2 (PER2) protein is the key step that determines the period of the mammalian circadian clock. Previous studies concluded that an unidentified kinase is required to prime PER2 for subsequent phosphorylation by casein kinase 1 (CK1), an essential clock component that is conserved from algae to humans. These subsequent phosphorylations stabilize PER2, delay its degradation, and lengthen the period of the circadian clock. Here, we perform a comprehensive biochemical and biophysical analysis of mouse PER2 (mPER2) priming phosphorylation and demonstrate, surprisingly, that CK1δ/ε is indeed the priming kinase. We find that both CK1ε and a recently characterized CK1δ2 splice variant more efficiently prime mPER2 for downstream phosphorylation in cells than the well-studied splice variant CK1δ1. While CK1 phosphorylation of PER2 was previously shown to be robust to changes in the cellular environment, our phosphoswitch mathematical model of circadian rhythms shows that the CK1 carboxyl-terminal tail can allow the period of the clock to be sensitive to cellular signaling. These studies implicate the extreme carboxyl terminus of CK1 as a key regulator of circadian timing.
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影响因子：
64.5
作者：
Chiu JC;Ko HW;Edery I
通讯作者：
Edery I
DOI：
10.1073/pnas.1721371115
发表时间：
2018-06-05
影响因子：
11.1
作者：
Fustin JM;Kojima R;Itoh K;Chang HY;Ye S;Zhuang B;Oji A;Gibo S;Narasimamurthy R;Virshup D;Kurosawa G;Doi M;Manabe I;Ishihama Y;Ikawa M;Okamura H
通讯作者：
Okamura H
DOI：
10.1073/pnas.0604511103
发表时间：
2006-07-11
影响因子：
11.1
作者：
Gallego, Monica;Eide, Erik J.;Forger, Daniel B.
通讯作者：
Forger, Daniel B.
影响因子：
4.8
作者：
GRAVES, PR;ROACH, PJ
通讯作者：
ROACH, PJ
影响因子：
3.7
作者：
Eng, Gracie Wee Ling;Edison;Virshup, David M.
通讯作者：
Virshup, David M.