From primordial clocks to circadian oscillators

Warintra Pitsawong, Ricardo A. P. Pádua, Timothy Grant, Marc Hoemberger, Renee Otten, Niels Bradshaw, Nikolaus Grigorieff and Dorothee Kern ()
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Warintra Pitsawong: Brandeis University
Ricardo A. P. Pádua: Brandeis University
Timothy Grant: Howard Hughes Medical Institute
Marc Hoemberger: Brandeis University
Renee Otten: Brandeis University
Niels Bradshaw: Brandeis University
Nikolaus Grigorieff: Howard Hughes Medical Institute
Dorothee Kern: Brandeis University

Nature, 2023, vol. 616, issue 7955, 183-189

Abstract: Abstract Circadian rhythms play an essential part in many biological processes, and only three prokaryotic proteins are required to constitute a true post-translational circadian oscillator1. The evolutionary history of the three Kai proteins indicates that KaiC is the oldest member and a central component of the clock2. Subsequent additions of KaiB and KaiA regulate the phosphorylation state of KaiC for time synchronization. The canonical KaiABC system in cyanobacteria is well understood3–6, but little is known about more ancient systems that only possess KaiBC. However, there are reports that they might exhibit a basic, hourglass-like timekeeping mechanism7–9. Here we investigate the primordial circadian clock in Rhodobacter sphaeroides, which contains only KaiBC, to elucidate its inner workings despite missing KaiA. Using a combination of X-ray crystallography and cryogenic electron microscopy, we find a new dodecameric fold for KaiC, in which two hexamers are held together by a coiled-coil bundle of 12 helices. This interaction is formed by the carboxy-terminal extension of KaiC and serves as an ancient regulatory moiety that is later superseded by KaiA. A coiled-coil register shift between daytime and night-time conformations is connected to phosphorylation sites through a long-range allosteric network that spans over 140 Å. Our kinetic data identify the difference in the ATP-to-ADP ratio between day and night as the environmental cue that drives the clock. They also unravel mechanistic details that shed light on the evolution of self-sustained oscillators.

Date: 2023
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DOI: 10.1038/s41586-023-05836-9

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