Molecular mechanisms of a biological clock

[Ace Pace]

Ars ahoy

While we may do our best to ignore it, we are all ruled by biological clocks that dictate what our body does at certain times. Biological clocks are not reserved for higher beings, they exist in everything from pond goo right up to human beings, and attempt to regulate a wide range of biochemical processes. At first, one would most likely assume that the molecular gadgetry that controls this would be a dizzying array of complex molecules, but a landmark study published by a team of Japanese researchers in 2005 showed that this was not the case. This team found that a scant three proteins—those that make up the biological clock in blue-green algae—will establish a 24-hour cycle when dropped into a beaker with adenosine triphosphate (ATP) with out any further external interaction.

Clearly this was a surprising result to people in the biological field. Now, a new study headed by Carl Johnson, a professor of biological science at Vanderbilt University has sought to understand how these three simple proteins are capable of establishing and operating on this 24-hour cycle. "We all thought the system was much more complicated and required feedback from the cell’s genetic machinery in order to work," said Prof. Johnson. Their results are published in the March 27 issue of the journal PLoS Biology.

To tackle this problem an interdisciplinary team of researchers—including biologists biophysicists, mathematicians, and microscopy experts—was formed to examine what makes this collection of three proteins—KaiA, KaiB, and KaiC—tick. What was found was that the largest protein, KaiC (pictured), was the major player in the time-keeping process. The daily cycle was, in part, created due to the regular increase and decrease in the amount of phosphate groups attached to the KaiC molecule. This binding and releasing of phosphate groups—known as phosphorylation and dephosphorylation, respectively—is a common method of protein function regulation. When KaiC had more and more phosphates attached to it, it would act in a different manner than when it had few phosphates attached, this would allow the protien to act as a clock to turn on and off various processes at various times which correlated with phosphorylation levels.

In the early stages, researchers envisioned a straightforward process where KaiA would begin to bind with KaiC and phosphorylation levels would rise for some time, then KaiB would begin to bind to this complex and phosphorylation levels would decrease until the complex fell apart and the cycle began anew. In an attempt to prove this, the researchers found that they were unable to isolate the KaiAC or KaiABC complex that they hypothesized would be important. What they later discovered was that the process was not so straightforward. The researchers found that all complexes existed simultaneously, but in various ratios at different points in the cycle. They were able to identify seven regimes—each with a characteristic process or composition—that in total, made up the 24-hour cycle.

They also realized that it was not the KaiA, KaiB, and KaiC proteins alone that controlled this process, but the building blocks of each protein played a role as well. It was found that in addition to the various complexes, that the KaiC was breaking into its monomeric building block units and reforming at various times throughout the cycle—adding another layer to the complexity. Using this data a mathematical model was created that attempted to explain the 24-hour cycle that was found. In the end the model was capable of explaining the process behind the cycle and why temperature could reset the system, messing with the biological clock.

What began as being identified as a very simple system—from a biological point of view—turns out to have rather complex chemical processes at its heart. The research team who worked on this plans to next turn their focus of how the proteins work together as a nanomachine to carry out their job.

[Sikon]

This team found that a scant three proteins—those that make up the biological clock in blue-green algae—will establish a 24-hour cycle when dropped into a beaker with adenosine triphosphate (ATP) with out any further external interaction.

That is interesting, for something so simple to maintain a 24-hour cycle.

The protein interaction described in the article apparently can provide a simple basis for 24-hour biological timekeeping, even while the whole system is more complex, a little like a computer running software at scheduled times has far more complexity than the quartz crystal oscillator in its clock alone yet that indirectly influences the operation of the whole computer.

There is more in total to the circadian rhythm system in animals like humans, such as part of the brain: the suprachiasmatic nucleus. For example, in humans, exposure to light is a factor in setting the biological clock.

Traditional treatment of patients with circadian rhythm disorders has been based on the premise that the suprachiasmatic nucleus, or the body’s internal clock, will only respond to bright light at a certain time of day. The fact that lower-intensity, short-wavelength blue light has been shown to be more effective than the most visible kinds of light in that regard is evidence that a separate photoreceptor system exists within the human eye, other than what is used for sight. Ultimately, color, intensity, and timing of light are all critical factors for stimulating the body clock, which regulates sleep patterns and other physiologic and behavioral functions.

From here.

Biological clocks have interesting effects, and here's a random example:

Enhanced Longevity in Tau Mutant Syrian Hamsters, Mesocricetus auratus
[...]
Abstract
The single-gene mutation tau in the Syrian hamster shortens the circadian period by about 20% in the homozygous mutant and simultaneously increases the mass-specific metabolic rate by about 20%. Both effects might be expected to lead to a change in longevity. To test such expectations, the life span of male and female hamsters from three genotypes (wild-type, heterozygous, and homozygous tau mutants, all derived from heterozygote crosses to randomize the genetic background) was recorded in constant darkness. Male hamsters lived significantly longer than females: the overall average life span was 96.9 weeks (SE = 2.5, n = 118) for males and 82.0 weeks (SE = 2.1, n = 99) for females. To our surprise, male and female homozygous mutant hamsters lived significantly longer rather than shorter compared to wild-types. For males, the difference between the two genotypes was on average 14%; for females, the difference was 16%. [...]

From here.