Phosphorylation of DNA-binding domains of CLOCK–BMAL1 complex for PER-dependent inhibition in circadian clock of mammalian cells

生物钟 细胞生物学 昼夜节律 磷酸化 生物钟 生物 DNA 遗传学 化学 神经科学
作者
Yuta Otobe,Eui Min Jeong,Shunsuke Ito,Yuta Shinohara,Nobuhiro Kurabayashi,Atsu Aiba,Yoshitaka Fukada,Jae Kyoung Kim,Hikari Yoshitane
出处
期刊:Proceedings of the National Academy of Sciences of the United States of America [National Academy of Sciences]
卷期号:121 (23) 被引量:4
标识
DOI:10.1073/pnas.2316858121
摘要

In mammals, CLOCK and BMAL1 proteins form a heterodimer that binds to E-box sequences and activates transcription of target genes, including Period ( Per) . Translated PER proteins then bind to the CLOCK–BMAL1 complex to inhibit its transcriptional activity. However, the molecular mechanism and the impact of this PER-dependent inhibition on the circadian clock oscillation remain elusive. We previously identified Ser38 and Ser42 in a DNA-binding domain of CLOCK as phosphorylation sites at the PER-dependent inhibition phase. In this study, knockout rescue experiments showed that nonphosphorylatable (Ala) mutations at these sites shortened circadian period, whereas their constitutive-phospho-mimetic (Asp) mutations completely abolished the circadian rhythms. Similarly, we found that nonphosphorylatable (Ala) and constitutive-phospho-mimetic (Glu) mutations at Ser78 in a DNA-binding domain of BMAL1 also shortened the circadian period and abolished the rhythms, respectively. The mathematical modeling predicted that these constitutive-phospho-mimetic mutations weaken the DNA binding of the CLOCK–BMAL1 complex and that the nonphosphorylatable mutations inhibit the PER-dependent displacement (reduction of DNA-binding ability) of the CLOCK–BMAL1 complex from DNA. Biochemical experiments supported the importance of these phosphorylation sites for displacement of the complex in the PER2-dependent inhibition. Our results provide direct evidence that phosphorylation of CLOCK–Ser38/Ser42 and BMAL1–Ser78 plays a crucial role in the PER-dependent inhibition and the determination of the circadian period.
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