Oral Presentation The 43rd Lorne Conference on Protein Structure and Function 2018

Dissecting the molecular basis of circadian timekeeping (#2)

Carrie Partch 1
  1. UCSC, Santa Cruz, CALIFORNIA, United States

Circadian clocks are an ancient evolutionary adaptation found across the domains of life, synchronizing behavior and physiology to the solar cycle for optimal fitness. The cyanobacterial circadian clock minimally consists of only three Kai proteins, yet it exhibits accurate, temperature-compensated timekeeping in the presence of ATP in vitro. Despite its relatively simple composition and the existence of high-resolution structures for its individual components, the lack of structural data on intermediate states formed by KaiBC and KaiABC complexes has limited our understanding of how this molecular oscillator measures the passing of time. KaiB undergoes a rare transition from its tetrameric ground state to a fold-switched, monomeric signaling state that is needed to bind KaiC and advance the clock into the evening1. To address the structural basis for this nighttime switch in activity, we locked KaiB into its fold-switched state, allowing us to solve several structures that demonstrate how KaiB docks cooperatively on the KaiC hexamer to recruit KaiA and regulate output signaling via two histidine kinases. These complexes identify signaling hotspots that control both timekeeping and output signaling2. Similar hotspots that depend on competition for mutually exclusive binding sites exist in the transcription-based mammalian clock, suggesting parallels in timekeeping strategies that may be utilized by diverse circadian clocks.

  1. 1Chang, Y.G., Cohen, S.E., Phong, C., Myers, W.K., Kim, Y.I., Tseng, R., Lin, J., Zhang, L., Boyd, J.S., Lee, Y., Kang, S., Lee, D., Li, S., Britt, R.D., Rust, M.J., Golden, S.S., LiWang, A. (2015) Circadian Rhythms. A protein fold switch joins the circadian oscillator to clock output in cyanobacteria. Science 349:324-8. 2Tseng, R.*, Goularte, N.F.*, Chavan, A.*, Luu, J., Cohen, S.E., Chang, Y.G., Heisler, J., Li, S, Michael, A.K., Tripathi, S., Golden, S.S., LiWang, A., Partch, C.L. (2017) Structural basis of the day-night transition in a bacterial circadian clock. Science, 355:1175-80.