Researchers better understand biological clock

Researchers at Harvard University and the Howard Hughes Medical Institute (HHMI) have discovered that a simple circadian clock found in some bacteria operates by the rhythmic addition and subtraction of phosphate groups at two key locations on a single protein. This phosphate pattern is influenced by two other proteins, driving phosphorylation to oscillate according to a remarkably accurate 24-hour cycle.

Writing this week in the journal Science, the scientists describe what causes a trio of proteins, if placed in a test tube with the common biochemical fuel ATP as a source of phosphate, to function as a minimalist biological clock of sorts, maintaining an accurate circadian rhythm for long periods of time.

The new Harvard work builds upon research reported in 2005 by biologist Takao Kondo and colleagues at Nagoya University in Japan. That team initially reported that a circadian clock could be reconstituted in a test tube solely with three proteins and ATP.

“The most striking feature of this circadian oscillator is its precision,” says Erin K. O’Shea, professor of molecular and cellular biology and chemistry and chemical biology in Harvard’s Faculty of Arts and Sciences (FAS), director of the FAS Center for Systems Biology, and Howard Hughes Medical Institute investigator. “Even in the absence of external cues — in total darkness — these minuscule protein-based clocks can maintain precision to a small fraction of a day over several weeks.”

O’Shea, postdoctoral researcher Michael J. Rust, graduate student Joseph S. Markson, and colleagues studied circadian rhythms in cyanobacteria, better known as blue-green algae. These simple organisms, responsible for some 70 percent of the Earth’s photosynthesis, devote most of their energies toward just two biological processes: photosynthesis and reproduction.

The scientists scrutinized the activity of three bacterial proteins known as KaiA, KaiB, and KaiC. They found that during the daytime, KaiC is cyclically phosphorylated at two amino acid residues: first at a specific threonine, and then at a specific serine. During nighttime hours, the two amino acids are dephosphorylated in the same order.

The KaiA protein promotes the phosphorylation of KaiC, and KaiB, sensing one of the phosphorylated forms of KaiC, blocks KaiA’s activity, creating an intricate biochemical dance that results in a nearly perfect 24-hour oscillation. The researchers’ subsequent mathematical analysis confirmed that this distinctive dynamic would, in fact, reproduce a circadian period.

The bacterial proteins studied by O’Shea, Rust, Markson, and colleagues are not known to exist in humans, but the researchers say their findings illuminate general feedback mechanisms that could serve to establish chronological oscillations in a whole host of organisms.

“It’s unknown whether such a mechanism is at the core of all circadian clocks,” says Rust, a postdoctoral researcher in Harvard’s Department of Molecular and Cellular Biology. “It’s the simplest chemical oscillator known, and we are looking at it as a possible model for other species.”

O’Shea says the 2005 finding by Kondo and colleagues that a cyanobacterial circadian clock could be recreated in a test tube using only three proteins and ATP surprised researchers because it showed that some circadian rhythms are driven solely by protein-protein interactions.

“It demonstrated that circadian clocks can operate independently of DNA and most cellular components, contradicting the previous prevailing theory that an entire organism was likely needed to maintain a clock,” she says.

O’Shea, Rust, and Markson’s co-authors are William S. Lane at Harvard and Daniel S. Fisher at Stanford University. The research was sponsored by HHMI and the National Science Foundation.

Source: Harvard University

Related stories:

Brainy genes, not brawn, key to success on mussel beach
It's hard being a mussel: you have to worry about hungry starfish and even hungrier humans, not to mention an environment that can change your body temperature 50 degrees Fahrenheit in just a few hours.
Variations in key genes increase Caucasians’ risk of heroin addiction
(PhysOrg.com) -- Sometimes, small changes do add up. In the case of addictive diseases, tiny variations in a few genes can increase or decrease the likelihood of some people developing a dependency on heroin. Now, by examining a select group of genetic variants in more than 400 former severe heroin addicts, Rockefeller University researchers have identified several genetic variations in American and Israeli Caucasians that influence the risk for becoming addicted to one of the world’s most powerful substances.
Benchmark cyanobacterium sequenced could be cheap renewable energy source
(PhysOrg.com) -- A team of researchers headed by biologists at Washington University in St. Louis has sequenced the genome of a unique bacterium that manages two disparate operations — photosynthesis and nitrogen fixation — in one little cell during two distinct cycles daily.
The first autism disease genes
The autistic disorder was first described, more than sixty years ago, by Dr. Leo Kanner of the Johns Hopkins Hospital (USA), who created the new label 'early infantile autism'. At the same time an Austrian scientist, Dr. Hans Asperger, described a milder form of the disorder that became known as Asperger Syndrome, characterised by higher cognitive abilities and more normal language function. Today, both disorders are classified in the continuum of 'Pervasive Developmental Disorders' (PDD), more often referred to as Autism Spectrum Disorders (ASD).
A snooze button for the circadian clock
We may use the snooze button to fine-tune our sleep cycles, but our cells have a far more meticulous and refined system. Humans, and most other organisms, have 24-hour rhythms that are regulated by a precise molecular clock that ticks inside every cell. After decades of study, researchers are still identifying all the gears involved in running this “circadian” clock and are working to put each of the molecular cogs in its place.
Model for angelman syndrome developed
A model for studying the genetics of Angelman syndrome, a neurological disorder that causes mental retardation and other symptoms in one out of 15,000 births, has been developed by biologists at The University of Texas at Austin.
Circadian rhythm-metabolism link discovered
UC Irvine researchers have found a molecular link between circadian rhythms – our own body clock – and metabolism. The discovery reveals new possibilities for the treatment of diabetes, obesity and other related diseases.
A mammalian clock protein responds directly to light
We all know that light effects the growth and development of plants, but what effect does light have on humans and animals? A new paper by Nathalie Hoang et al., published in PLoS Biology this week, explores this question by examining cryptochromes in flies, mice, and humans. In plants, cryptochromes are photoreceptor proteins which absorb and process blue light for functions such as growth, seedling development, and leaf and stem expansion.

News discussion:

General Science news