A Slow Conformational Switch in the BMAL1 Transactivation Domain Modulates Circadian Rhythms.
A Slow Conformational Switch in the BMAL1 Transactivation Domain Modulates Circadian Rhythms.
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DOI：
10.1016/j.molcel.2017.04.011
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发表时间：
2017-05-18
期刊：
影响因子：
16
通讯作者：
Partch CL
中科院分区：
文献类型：
--
作者：
Gustafson CL;Parsley NC;Asimgil H;Lee HW;Ahlbach C;Michael AK;Xu H;Williams OL;Davis TL;Liu AC;Partch CL
BMAL 1（Brain and muscle ARNT-like 1）的C-末端反式激活结构域（C-terminal transactivation domain，C-terminal）是转录共激活因子和抑制因子的调节中心，其竞争结合并因此有助于哺乳动物昼夜节律钟的周期确定。在这里，我们报告发现两个不同的构象状态，缓慢地交换内的动态控制时序。这种二进制开关的结果顺/反异构化的高度保守的Trp-Pro酰亚胺键在一个地区的的正常昼夜节律的时间保持所需的。顺式和反式异构体与转录调控因子相互作用，表明异构化可以在体内组装调控复合物中发挥作用。为此，我们表明，锁定开关到反式异构体导致缩短昼夜节律周期。此外，异构化是由亲环蛋白家族的肽基脯氨酰异构酶，突出了在周期确定的BMAL 1蛋白质动力学调节的潜力。
The C-terminal transactivation domain (TAD) of BMAL1 (Brain and muscle ARNT-like 1) is a regulatory hub for transcriptional coactivators and repressors that compete for binding and consequently contributes to period determination of the mammalian circadian clock. Here, we report the discovery of two distinct conformational states that slowly exchange within the dynamic TAD to control timing. This binary switch results from cis/trans isomerization about a highly conserved Trp-Pro imide bond in a region of the TAD that is required for normal circadian timekeeping. Both cis and trans isomers interact with transcriptional regulators, suggesting that isomerization could serve a role in assembling regulatory complexes in vivo. Towards this end, we show that locking the switch into the trans isomer leads to shortened circadian periods. Furthermore, isomerization is regulated by the cyclophilin family of peptidyl-prolyl isomerases, highlighting the potential for regulation of BMAL1 protein dynamics in period determination.