Noncanonical FK506-binding protein BDBT binds DBT to enhance its circadian function and forms foci at night.
Noncanonical FK506-binding protein BDBT binds DBT to enhance its circadian function and forms foci at night.
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DOI：
10.1016/j.neuron.2013.08.004
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发表时间：
2013-11-20
期刊：
影响因子：
16.2
通讯作者：
Price JL
中科院分区：
文献类型：
--
作者：
Fan JY;Agyekum B;Venkatesan A;Hall DR;Keightley A;Bjes ES;Bouyain S;Price JL
激酶DOUBLETIME是果蝇昼夜节律钟的主要调节因子，但调节其活性的机制仍不清楚。对DOUBLETIME相互作用物的蛋白质组学分析鉴定出一种未研究的蛋白质，命名为CG17282。RNA干扰介导的CG17282基因敲低产生了行为不稳定性和长周期、高水平的低磷酸化核周期和磷酸化双时间。果蝇中DOUBLETIME的过表达抑制了这些表型，而S2细胞中CG17282的过表达增强了DOUBLETIME依赖性周期的降解，表明CG17282刺激了DOUBLETIME的昼夜节律功能。在光感受器中，CG17282在周期和双倍时间依赖性胞质病灶中有节奏地积累。最后，结构分析表明，CG17282是一种非经典的FK506结合蛋白，具有无活性的肽脯氨酰异构酶结构域，可结合DOUBLETIME和tetratricopeptide重复序列，可促进较大蛋白质复合物的组装。我们命名为CG17282 Bride of Doubletime，并将其确定为DOUBLETIME对PERIOD影响的介体，最有可能在调节PERIOD核积聚的胞质病灶中。
The kinase DOUBLETIME is a master regulator of the Drosophila circadian clock, yet the mechanisms regulating its activity remain unclear. A proteomic analysis of DOUBLETIME interactors led to the identification of an unstudied protein designated CG17282. RNAi-mediated knock-down of CG17282 produced behavioral arrhythmicity and long periods, high levels of hypophosphorylated nuclear PERIOD and phosphorylated DOUBLETIME. Overexpression of DOUBLETIME in flies suppresses these phenotypes and overexpression of CG17282 in S2 cells enhances DOUBLETIME-dependent PERIOD degradation, indicating that CG17282 stimulates DOUBLETIME’s circadian function. In photoreceptors, CG17282 accumulates rhythmically in PERIOD- and DOUBLETIME-dependent cytosolic foci. Finally, structural analyses demonstrated CG17282 is a noncanonical FK506-binding protein with an inactive peptide prolyl-isomerase domain that binds DOUBLETIME and tetratricopeptide repeats that may promote assembly of larger protein complexes. We have named CG17282 Bride of Doubletime and established it as a mediator of DOUBLETIME’s effects on PERIOD, most likely in cytosolic foci that regulate PERIOD nuclear accumulation.
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