Cryptochrome 1 regulates the circadian clock through dynamic interactions with the BMAL1 C terminus

被引:121
作者
Xu, Haiyan [1 ,2 ]
Gustafson, Chelsea L. [3 ]
Sammons, Patrick J. [3 ]
Khan, Sanjoy K. [1 ]
Parsley, Nicole C. [3 ]
Ramanathan, Chidambaram [1 ]
Lee, Hsiau-Wei [3 ]
Liu, Andrew C. [1 ,2 ]
Partch, Carrie L. [3 ,4 ]
机构
[1] Univ Memphis, Dept Biol Sci, Memphis, TN 38152 USA
[2] Univ Memphis, Feinstone Ctr Genom Res, Memphis, TN 38152 USA
[3] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA
[4] Univ Calif San Diego, Ctr Circadian Biol, San Diego, CA 92103 USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
CASEIN KINASE 1; SECONDARY STRUCTURE; FEEDBACK REPRESSION; MOLECULAR-BASIS; PROTEIN; TRANSACTIVATION; BINDING; PERIOD; IDENTIFICATION; MECHANISM;
D O I
10.1038/nsmb.3018
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
The molecular circadian clock in mammals is generated from transcriptional activation by the bHLH-PAS transcription factor CLOCK-BMAL1 and subsequent repression by PERIOD and CRYPTOCHROME (CRY). The mechanism by which CRYs repress CLOCK-BMAL1 to close the negative feedback loop and generate 24-h timing is not known. Here we show that, in mouse fibroblasts, CRY1 competes for binding with coactivators to the intrinsically unstructured C-terminal transactivation domain (TAD) of BMAL1 to establish a functional switch between activation and repression of CLOCK-BMAL1. TAD mutations that alter affinities for co-regulators affect the balance of repression and activation to consequently change the intrinsic circadian period or eliminate cycling altogether. Our results suggest that CRY1 fulfills its role as an essential circadian repressor by sequestering the TAD from coactivators, and they highlight regulation of the BMAL1 TAD as a critical mechanism for establishing circadian timing.
引用
收藏
页码:476 / U70
页数:11
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