Earth’s Daily Rotation Period Encoded in an Atomic-level Protein Structure

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The clock in a clock: how ancient cyanobacteria record earth’s time with small clocks

Biological clocks are tiny pacemakers that set the pace of an organism’s biochemical processes to keep time with the earth’s rotation period. This diurnal time-keeping device has appeared to evolve independently in a wide range of organisms from ancient cyanobacteria to modern human beings, raising questions regarding the origins and importance of this synchronization with the earth’s 24- hour circadian cycle, and the molecular mechanisms underlying it.

A collaborative group of research scientists from Japan have attempted to answer the latter question by dissecting a key protein in the cyanobacterial circadian clock. Synechoccosus elongatus is a blue green algae that has the simplest known clock comprising three proteins called KaiA, KaiB and KaiC. A previous study in 2005 showed that these three proteins when mixed together in a test tube, along with ATP, were capable of keeping time on their own. This was a surprise since most clocks from other organisms require an elaborate feedback loop to its genetic machinery to establish a circadian rhythm. This is often the case since biochemical processes occur within a timescale of picoseconds to seconds, requiring a tight negative feedback loop to ‘slow down’ their periodicity to a circadian pattern. A further question was raised- how is it that the earth’s ‘slow’ rotation period is recorded within the components of a test tube?

Long-time, for C- KaiC and the earth’s rotation period. Credit: IMS/NINS
Long-time, for C- KaiC and the earth’s rotation period. Credit: IMS/NINS

The current study identified and postulated that it was the relatively slow ATPase hydrolysis activity of KaiC that could be the basic timing cue for the cyanobacterial clock, since it exhibited near-circadian oscillations in its activity even in the absence of KaiA and KaiB. To discover the structural basis of this slowness relative to other well-studied ATPases, high resolution X-ray crystallography was used to analyze the ATP-hydrolysis states of the KaiC hexamer. The study revealed two significant molecular mechanisms by which a single protein has adapted to keep time.

During ATP hydrolysis a water molecule attacks the ultimate phosphoryl group on ATP, for which it is required to occupy a stable and optimal position with respect to the ATP moiety. In KaiC, this water is sterically hindered by residues on the polypeptide chain from occupying the most favorable position for lytic attack, thereby significantly dampening the rate of ATP hydrolysis. In addition, this hydrolysis is coupled to an isomerization event within the KaiC polypeptide chain, a process which in itself requires significant energy. In combination, the entire KaiC ATP-hydrolysis process has to overcome a higher free energy barrier than is typical for other ATPases. This ‘slowness’ is translated to cycles of phosphorylation that alter interactions with other clock proteins, indirectly generating a circadian rhythm.

The study is the first to demonstrate the atomic-level adaptation of a single protein to generate a large time-scale periodicity by subtly modifying its structure.

The original paper can be accessed here.

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