The inner workings of the circadian clock

Phong, C.; Markson, J.S.; Wilhoite, C.; Rust, M. J.

Robust and tunable circadian rhythms from differentially sensitive catalytic domains

Proc. Natl. Acad. Sci. Epub 2012 December 31. doi: 10.1073/pnas.1212113110

Circadian clocks synchronize the body’s behavior with the 24-hour rotation of the Earth.  To do this, these biological time-keeping systems must have two properties that are, at least on the surface, conflicting.  They must be able to keep the period of oscillation of the clock to 24 hours over a wide range of environmental conditions – that is, to be robust over a wide range of environmental conditions.  However, changes in the environment must be capable of efficiently resetting the phase of the clock, so that, for instance, one may adapt to relocating to a different time zone. Without these properties, the clock can become desynchronized with the environment, condition similar to a jet lag-like state that is associated with decreased fitness and disease.

To understand the molecular mechanisms underlying these properties, IGSB Core faculty Michael Rust studies the circadian clock of the cyanobacterium Synechococcus elongates, the simplest known.  In this organism, three proteins, KaiA, KaiB and KaiC, maintain a robust ~24 hour period based on stable oscillations in KaiC phosphorylation and are capable of shifting phase in response to metabolic signals.  Dr. Rust and colleagues find that both robustness and adaptability of the clock are determined by the two enzymatic domains of KaiC.  One of the domains, CII, phosphorylates itself in response to input signals.  CI, a domain of previously unknown function, is insulated from input signals and sets a slow, constant timescale for the interaction between KaiC and the negative regulator KaiB. By building mathematical models of this system, the authors find that this two-domain architecture is needed to get the combination of robust period and tunable phase in the circadian clock.  These models will help to illuminate the structures of the clock networks in humans and other organisms where input-sensitive and input-insensitive feedback loops may also be required for proper function.

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