article published yes Chelsea L. Gustafson author Nicole C. Parsley author Hande Asimgil author Hsiau-Wei Lee author Christopher Ahlbach author Alicia Kathleen Michael author 6437c950-2a03-11ee-914d-d6476dd7b75c Haiyan Xu author Owen L. Williams author Tara L. Davis author Andrew C. Liu author Carrie L. Partch author 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. Toward 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. Elsevier2017 eng Cell BiologyMolecular Biology 1097-276510.1016/j.molcel.2017.04.011 664447-457.e7 yes Gustafson, Chelsea L., Nicole C. Parsley, Hande Asimgil, Hsiau-Wei Lee, Christopher Ahlbach, Alicia K. Michael, Haiyan Xu, et al. “A Slow Conformational Switch in the BMAL1 Transactivation Domain Modulates Circadian Rhythms.” <i>Molecular Cell</i>. Elsevier, 2017. <a href="https://doi.org/10.1016/j.molcel.2017.04.011">https://doi.org/10.1016/j.molcel.2017.04.011</a>. Gustafson CL, Parsley NC, Asimgil H, et al. A slow conformational switch in the BMAL1 transactivation domain modulates circadian rhythms. <i>Molecular Cell</i>. 2017;66(4):447-457.e7. doi:<a href="https://doi.org/10.1016/j.molcel.2017.04.011">10.1016/j.molcel.2017.04.011</a> Gustafson, Chelsea L., et al. “A Slow Conformational Switch in the BMAL1 Transactivation Domain Modulates Circadian Rhythms.” <i>Molecular Cell</i>, vol. 66, no. 4, Elsevier, 2017, p. 447–457.e7, doi:<a href="https://doi.org/10.1016/j.molcel.2017.04.011">10.1016/j.molcel.2017.04.011</a>. Gustafson, C. L., Parsley, N. C., Asimgil, H., Lee, H.-W., Ahlbach, C., Michael, A. K., … Partch, C. L. (2017). A slow conformational switch in the BMAL1 transactivation domain modulates circadian rhythms. <i>Molecular Cell</i>. Elsevier. <a href="https://doi.org/10.1016/j.molcel.2017.04.011">https://doi.org/10.1016/j.molcel.2017.04.011</a> C. L. Gustafson <i>et al.</i>, “A slow conformational switch in the BMAL1 transactivation domain modulates circadian rhythms,” <i>Molecular Cell</i>, vol. 66, no. 4. Elsevier, p. 447–457.e7, 2017. C.L. Gustafson, N.C. Parsley, H. Asimgil, H.-W. Lee, C. Ahlbach, A.K. Michael, H. Xu, O.L. Williams, T.L. Davis, A.C. Liu, C.L. Partch, Molecular Cell 66 (2017) 447–457.e7. Gustafson CL, Parsley NC, Asimgil H, Lee H-W, Ahlbach C, Michael AK, Xu H, Williams OL, Davis TL, Liu AC, Partch CL. 2017. A slow conformational switch in the BMAL1 transactivation domain modulates circadian rhythms. Molecular Cell. 66(4), 447–457.e7. 151552024-03-21T07:56:01Z2024-03-25T12:19:20Z