The human CRY1 tail controls circadian timing by regulating its association with CLOCK:BMAL1
The human CRY1 tail controls circadian timing by regulating its association with CLOCK:BMAL1
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DOI：
10.1073/pnas.1920653117
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发表时间：
2020-11-10
影响因子：
11.1
通讯作者：
Partch, Carrie L.
中科院分区：
文献类型：
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作者：
Parico, Gian Carlo G.;Perez, Ivette;Partch, Carrie L.
昼夜节律是由互锁的转录-翻译反馈回路产生的，该回路建立了类似于24小时的细胞自主生物计时。核心时钟基因的突变会改变它们的稳定性或彼此的亲和力，从而导致昼夜节律周期的变化。人类CRY1A11突变体延长了昼夜节律周期，导致延迟睡眠阶段障碍（DSPD），其特征是睡眠开始得很晚。CRY1是一种与转录因子CLOCK:BMAL1结合抑制其活性并关闭核心反馈回路的抑制因子。我们之前展示了CRY1的PHR（光解酶同源区）结构域如何与CLOCK和BMAL1上的不同位点相互作用，从而从共激活子中分离出交易激活结构域。然而，A11变体改变了PHR下游CRY1的内在无序尾部。我们在这里表明，CRY1尾部，特别是由外显子11编码的区域，调节了PHR结构域对CLOCK:BMAL1的亲和力。外显子11中的phrr结合表位是破坏CRY1与亚基CLOCK之间相互作用的必要和充分条件。更重要的是，phrr -tail的相互作用在平行CRY2中是保守的，当其中一个CRY与昼夜节律共抑制因子PERIOD2结合时，这种相互作用会减少。哺乳动物CRY1尾的这种自我调节作用的发现以及两种哺乳动物隐色素中phr1尾相互作用的保守性，突出了植物和昆虫隐色素的功能保守性，它们也利用phr1尾相互作用可逆地控制其活性。
Circadian rhythms are generated by interlocked transcription- translation feedback loops that establish cell-autonomous biological timing of similar to 24 h. Mutations in core clock genes that alter their stability or affinity for one another lead to changes in circadian period. The human CRY1A11 mutant lengthens circadian period to cause delayed sleep phase disorder (DSPD), characterized by a very late onset of sleep. CRY1 is a repressor that binds to the transcription factor CLOCK:BMAL1 to inhibit its activity and close the core feedback loop. We previously showed how the PHR (photolyase homology region) domain of CRY1 interacts with distinct sites on CLOCK and BMAL1 to sequester the transactivation domain from coactivators. However, the A11 variant alters an intrinsically dis ordered tail in CRY1 downstream of the PHR. We show here that the CRY1 tail, and in particular the region encoded by exon 11, modulates the affinity of the PHR domain for CLOCK:BMAL1. The PHR-binding epitope in exon 11 is necessary and sufficient to disrupt the interaction between CRY1 and the subunit CLOCK. More over, PHR-tail interactions are conserved in the paralog CRY2 and reduced when either CRY is bound to the circadian corepressor PERIOD2. Discovery of this autoregulatory role for the mammalian CRY1 tail and conservation of PHR-tail interactions in both mammalian cryptochromes highlights functional conservation with plant and insect cryptochromes, which also utilize PHR-tail interactions to reversibly control their activity.