The timekeeper’s protecting embrace
The interactions between two clock proteins that control life’s daily rhythms are revealed in detail.
Since the very simplest organisms emerged on earth, the rhythms of life have been synchronized with the rising and setting of the sun. Even the most basic life forms have internal clocks that help them to maintain daily routines and adapt to shifting seasons. In animals, these internal clocks regulate processes such as the release of hormones that wake an animal up and the expression of genes necessary to carry out the activities of daily life. Later on, the clocks then trigger the release of hormones that cause drowsiness and the expression of the genes that are active during rest.
In mammals, these internal circadian rhythms are maintained by a feedback loop governed by four key proteins. Two of these proteins — CLOCK and BMAL1 — work together to begin a process called transcription, whereby sections of DNA are used as a template to copy the information needed to make a protein. The two activating proteins CLOCK and BMAL1 recognize the sections of DNA where the genes that are controlled by the circadian clock are located and selectively turn on the expression of those genes.
Expression of the two other key circadian proteins — Period and Cryptochrome — is switched on by CLOCK and BMAL1. As Period and Cryptochrome proteins accumulate, they begin to inhibit the activity of CLOCK and BMAL1, helping to reduce the rate at which the circadian genes are transcribed as the day progresses.
Shannon Nangle, Clark Rosensweig and co-workers provide new insights into how the Period and Cryptochrome proteins interact with each other, using X-ray crystallography to reveal the molecular level details of the bond between the two proteins. Period stretches out as it ‘embraces’ Cryptochrome. One end of the Period protein then tucks into part of the Cryptochrome structure that is next to a large pocket. This pocket is where the Cryptochrome protein binds to CLOCK and BMAL1, suggesting that Period can influence whether this binding occurs.
The other end of the Period protein covers one end of the Cryptochrome protein. By doing so, enzymes cannot bind there, and so cannot break down Cryptochrome. Shannon Nangle, Clark Rosensweig and co-workers also discovered that a finger-like projection that includes a zinc ion acts as a clasp, strengthening the bond between Period and Cryptochrome.
These findings help to demonstrate how Period proteins act as a timekeeper that regulates how long Cryptochrome can turn down the activity of CLOCK and BMAL1. A deeper understanding of the molecular choreography among the four clock proteins holds promise for developing medications to treat the sleep disorders and circadian clock disruptions associated with a modern lifestyle.
To find out more
Read the eLife research paper on which this story is based: “Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex” (August 15, 2014).
eLife is an open-access journal that publishes outstanding research in the life sciences and biomedicine.