From primordial clocks to circadian oscillators
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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 oscillator 1 . The evolutionary history of the three Kai proteins indicates that KaiC is the oldest member and a central component of the clock 2 . Subsequent additions of KaiB and KaiA regulate the phosphorylation state of KaiC for time synchronization. The canonical KaiABC system in cyanobacteria is well understood 3–6 , 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 mechanism 7–9 . 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is formed by the carboxy-terminal extension of KaiC and serves as an ancient regulatory moiety that is later superseded by KaiA.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.
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KaiBRS switches between two monomeric states as found using NMR.
“We used KaiB from R. sphaeroides32 (hereafter KaiBRS) for this test, which we found using NMR switches between two monomeric states, to eliminate the complicating factor of mutations contributing to ground-state tetramerization in the previously studied KaiBTE (ref. 5).”
From Predicting multiple conformations via sequence clustering and AlphaFold2 (2024) · cites this paper as [32]
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- [14]Aoki, S. & Onai, K. in Bacterial Circadian Programs (eds Mackey S. R. Ditty J. L. & Johnson C. H.) 259–282 (Springer, 2009).
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Predicting multiple conformations via sequence clustering and AlphaFold2
Wayment-Steele, H. K., Ojoawo, A., Otten, R., Apitz, J. M., Pitsawong, W., Hömberger, M., Ovchinnikov, S., Colwell, L., & Kern, D. (2024) · Nature · doi:10.1038/s41586-023-06832-9 · Cited by 545 · see citing works
Self-citation
- Authors
- Pitsawong, W., Pádua, R. A. P., Grant, T., Hoemberger, M., Otten, R., Bradshaw, N., Grigorieff, N., & Kern, D.
- Affiliations
- Howard Hughes Medical Institute (US)
- Brandeis University (US)
- Corresponding author
- Kern, Dorothee
- ORCID
- Venue
- Nature
- Published
- 2023-03-22
- Volume
- 616
- Issue
- 7955
- Pages
- 183-189
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC10076222
- OpenAlex
- W4353055416
- Cited by
- 37
- References
- 69
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 10 · 2023: 6 · 2021: 1
- FWCI
- 5.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute (P30 GM124169-01, DE-AC02-05CH11231)
- U.S. Department of Energy (-AC02-05CH11231, Contract No. DE-AC02-05-CH11231, 05CH11231, No. DE-AC02-05-CH11231, DE AC02 05CH11231, GM124169, DE-AC02-)
- Brandeis University
- National Institutes of Health (SCR_019063, DE-AC02–05CH11231, P30-GM124169-01, GM124169)
- Office of Science (No. DE-AC02- 05-CH11231, DEAC02–05CH11231, AC02-05CH11231, DE-AC02, Contract No. DE-AC02-05CH11231)
- National Institute of General Medical Sciences (DE-AC02-05CH11231, GM124169-01, GM124169, P30GM124169)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Light effects on plants
- Physical Sciences › Computer Science › Computer Networks and Communications › Nonlinear Dynamics and Pattern Formation
- Keywords
- circadian clock, KaiC, KaiA, Rhodobacter sphaeroides, allosteric networks, phosphorylation
- MeSH terms
- Adenosine Diphosphate, Adenosine Triphosphate, Allosteric Regulation, Bacterial Proteins, Circadian Rhythm, Kinetics, Phosphorylation, Protein Conformation, Rhodobacter sphaeroides, Protein Folding, Crystallography, X-Ray, Cryoelectron Microscopy, Circadian Clocks
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