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From primordial clocks to circadian oscillators

Warintra Pitsawong, Ricardo A. P. Pádua, Timothy Grant, Marc Hoemberger, Renee Otten, Niels Bradshaw, Nikolaus Grigorieff, Dorothee Kern
doi: https://doi.org/10.1101/2022.11.28.518275
Warintra Pitsawong
1Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, 415 South Street, Waltham, MA 02454, USA
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Ricardo A. P. Pádua
1Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, 415 South Street, Waltham, MA 02454, USA
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Timothy Grant
2Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Dr, Ashburn, VA 20147, USA
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Marc Hoemberger
1Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, 415 South Street, Waltham, MA 02454, USA
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Renee Otten
1Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, 415 South Street, Waltham, MA 02454, USA
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Niels Bradshaw
3Department of Biochemistry, Brandeis University, 415 South Street, Waltham, MA 02454, USA
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Nikolaus Grigorieff
2Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Dr, Ashburn, VA 20147, USA
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Dorothee Kern
1Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, 415 South Street, Waltham, MA 02454, USA
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  • For correspondence: dkern@brandeis.edu
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Abstract

Circadian rhythms play an essential role in many biological processes and surprisingly only three prokaryotic proteins are required to constitute a true post-translational circadian oscillator. The evolutionary history of the three Kai proteins indicates that KaiC is the oldest member and central component of the clock, with subsequent additions of KaiB and KaiA to regulate its phosphorylation state for time synchronization. The canonical KaiABC system in cyanobacteria is well understood, but little is known about more ancient systems that possess just KaiBC, except for reports that they might exhibit a basic, hourglass-like timekeeping mechanism. Here, we investigate the primordial circadian clock in Rhodobacter sphaeroides (RS) that contains only KaiBC to elucidate its inner workings despite the missing KaiA. Using a combination X-ray crystallography and cryo-EM we find a novel dodecameric fold for KaiCRS where two hexamers are held together by a coiled-coil bundle of 12 helices. This interaction is formed by the C-terminal extension of KaiCRS and serves as an ancient regulatory moiety later superseded by KaiA. A coiled-coil register shift between daytime- and nighttime-conformations is connected to the phosphorylation sites through a long-range allosteric network that spans over 160 Å. Our kinetic data identify the difference in ATP-to-ADP ratio between day and night as the environmental cue that drives the clock and further unravels mechanistic details that shed light on the evolution of self-sustained oscillators.

Competing Interest Statement

D.K. is co-founder of Relay Therapeutics and MOMA Therapeutics. The remaining authors declare no competing interests.

Footnotes

  • Remove the line number that overlap with the figure legend

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 29, 2022.
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From primordial clocks to circadian oscillators
Warintra Pitsawong, Ricardo A. P. Pádua, Timothy Grant, Marc Hoemberger, Renee Otten, Niels Bradshaw, Nikolaus Grigorieff, Dorothee Kern
bioRxiv 2022.11.28.518275; doi: https://doi.org/10.1101/2022.11.28.518275
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From primordial clocks to circadian oscillators
Warintra Pitsawong, Ricardo A. P. Pádua, Timothy Grant, Marc Hoemberger, Renee Otten, Niels Bradshaw, Nikolaus Grigorieff, Dorothee Kern
bioRxiv 2022.11.28.518275; doi: https://doi.org/10.1101/2022.11.28.518275

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