Aichi, Japan—Researchers from the Institute for Molecular Science (IMS)/SOKENDAI and Kyushu University have revealed the molecular mechanism behind the precise “ticking” of the circadian clock in cyanobacteria. Their study, published in PNAS Nexus on April 28, 2025, demonstrates how the clock protein KaiC controls chemical reactions with remarkable timing, acting like the hand of a clock that pauses before moving at the right moment.
The Simplicity and Mystery of Cyanobacteria’s Clock
Most organisms, from bacteria to humans, rely on internal circadian clocks to adapt to Earth’s daily rotation. Cyanobacteria stand out because their clock, comprising three proteins (KaiA, KaiB, and KaiC), is the only one fully reproducible in a test tube. For decades, scientists observed KaiC’s 24-hour cycle of phosphorylation (adding phosphate groups) and dephosphorylation (removing them), but the exact trigger for these reactions remained unknown.
Key Discovery: KaiC’s Independent “Ticking”
Led by Assistant Professor Yoshihiko Furuike and Professor Shuji Akiyama (IMS/SOKENDAI) and Associate Professor Toshifumi Mori (Kyushu University), the team isolated KaiC to study its behavior without KaiA and KaiB. Surprisingly, they found that KaiC alone could slowly bind phosphate, revealing that the core timing mechanism lies within KaiC itself.
Using near-atomic-resolution structural data, the researchers simulated the phosphorylation process. They discovered that subtle shifts in specific amino acids—glutamate and arginine—act as molecular triggers. These residues function like a gate, pausing the reaction until the precise moment the “clock hand” should move.
Broader Implications for Biology and Medicine
This mechanism isn’t unique to cyanobacteria. Phosphorylation regulates circadian clocks in humans and other organisms, offering insights into universal biological timekeeping. Additionally, since phosphorylation is linked to diseases, understanding how proteins control reaction timing could advance drug design and biomedical research.
While this study clarifies phosphorylation, dephosphorylation remains a puzzle—a key focus for future work. The findings open new avenues for exploring the fundamental principles of life’s rhythms.
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