How Protein Molecules Drive Circadian Rhythms

The exceptionally slow oscillation of the KaiC molecule has been explained, and with it, how we have circadian rhythms. Jawahar Swaminathan/European Bioinformatics Institute via wikimedia commons

The slow oscillation of the protein that controls the circadian rhythms of cynobacteria has been explained. The KaiC protein has a period similar to the length of a day, vastly longer than similar molecules. A related process is thought to drive our own daily cycle, and possibly explain why humans seem slightly out of step with the world on which they live.

Whether nocturnal or diurnal, animals operate on a cycle matching the Earth's rotation, waking and sleeping at roughly the same time each day. Plants operate similarly. This isn't simply a response to being exposed to light and darkness, since these rhythms have been shown to have a genetic component.

So how does the body encode this period?

Proteins produced by two genes have been shown to degrade over a period of roughly 24 hours, so that when they drop below a certain point, the body's clock restarts. However, decay is a pretty rough timing mechanism. Molecular oscillation is far more precise, but most molecules do so on periods of fractions of seconds.

KaiC is an exception. While its extraordinarily long period and role in setting cynobacterial body clocks has been known for some time, two new papers in the journal Science shed light on exactly how this occurs. A team from three University of California campuses announced that “The clock of cynobacteria is driven by a three-protein oscillator comprised of KaiA, KaiB and KaiC, which together generate a circadian rhythm.” 

"If you mix cyanobacterial clock proteins in a test tube with an energy source, the  literally starts ticking," said senior author Professor Andy LiWang of UC Merced. "You can tell time by it. How do these clocks manage to go at a 24-hour pace?" 

The question has been partially answered by researchers from four Japanese institutions who point out that “Circadian clocks generate slow and ordered cellular dynamics, but consist of fast-moving bio-macromolecules; consequently, the origins of the overall slowness remain unclear.” However, they report, “We identified the adenosine triphosphate catalytic region (ATPase) in the N-terminal half of the clock protein KaiC as the minimal pacemaker that controls the in vivo frequency of the cyanobacterial clock.”

The reason KaiC operates so much more slowly than most biomolecules is due to the way in which a water molecule becomes trapped within KaiC's crystal structure. “A water molecule is prevented from attacking into the ideal position for the ATP hydrolysis by a steric hindrance near ATP phosphoryl groups,” says first author Dr. Jun Abe of the Institute of Molecular Science. The consequence is a cycle up to a million times slower than that of other ATPase molecules and, handily for reliable timekeeping, it isn't even affected by temperature.

While KaiC's cycle is close enough to an Earth day to be useful for living things in need of an appropriate timekeeping device, its frequency is actually 0.91 times a day, giving a cycle of 26.4 hours. Intriguingly, it has been observed that most humans default to a cycle slightly longer than a 24-hour day, although the length is different for other species.

KaiC's role has only been demonstrated for single-celled organisms, but both teams expect that matching molecules that perform a similar function can be found for multicellular life.

Perhaps one day, as the moon's drag slows the Earth's rotation, the planet's day will come to match the period of the molecule within us.

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