NEMO/NLK phosphorylates PERIOD to initiate a time-delay phosphorylation circuit that sets circadian clock speed.
NEMO/NLK phosphorylates PERIOD to initiate a time-delay phosphorylation circuit that sets circadian clock speed.
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DOI：
10.1016/j.cell.2011.04.002
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发表时间：
2011-04-29
期刊：
影响因子：
64.5
通讯作者：
Edery I
中科院分区：
文献类型：
--
作者：
Chiu JC;Ko HW;Edery I
动物生物钟的速度与复杂的磷酸化程序密切相关，这些程序驱动PERIOD（PER）蛋白水平的每日周期。使用果蝇，我们确定了一个时间延迟电路的基础上分级磷酸化，控制每日下降的PER丰度。NEMO/NLK激酶在PER上的per-short结构域的磷酸化刺激在几个附近位点的DOUBLETIME（DBT/CK 1 δ/ε）磷酸化。这种多位点磷酸化以空间定向和分级的方式发挥作用，以延迟DBT在PER上其他更远端位点的渐进磷酸化，包括被F-box蛋白SLIMB/β-TrCP识别和蛋白酶体降解所需的位点。高度磷酸化的PER具有更开放的结构，这表明全球磷酸化的逐步增加通过缓慢增加PER对降解的敏感性而有助于计时机制。我们的研究结果确定NEMO作为一个时钟激酶，并表明，功能不同的磷酸簇之间的远程相互作用合作，以设置时钟速度。
The speed of circadian clocks in animals is tightly linked to complex phosphorylation programs that drive daily cycles in the levels of PERIOD (PER) proteins. Using Drosophila we identify a time-delay circuit based on hierarchical phosphorylation that controls the daily downswing in PER abundance. Phosphorylation by the NEMO/NLK kinase at the per-short domain on PER stimulates phosphorylation by DOUBLETIME (DBT/CK1δ/ε) at several nearby sites. This multi-site phosphorylation operates in a spatially-oriented and graded manner to delay progressive phosphorylation by DBT at other more distal sites on PER, including those required for recognition by the F-box protein SLIMB/β-TrCP and proteasomal degradation. Highly phosphorylated PER has a more open structure, suggesting that progressive increases in global phosphorylation contribute to the timing mechanism by slowly increasing PER susceptibility to degradation. Our findings identify NEMO as a clock kinase and demonstrate that long-range interactions between functionally distinct phospho-clusters collaborate to set clock speed.
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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：
64.8
作者：
Ko, HW;Jiang, J;Edery, I
通讯作者：
Edery, I
DOI：
10.1073/pnas.91.6.2260
发表时间：
1994-03-15
影响因子：
11.1
作者：
EDERY, I;ZWIEBEL, LJ;ROSBASH, M
通讯作者：
ROSBASH, M
影响因子：
3.5
作者：
KONOPKA, RJ;HAMBLENCOYLE, MJ;HALL, JC
通讯作者：
HALL, JC
影响因子：
18.2
作者：
Allada R;Chung BY
通讯作者：
Chung BY