A new study links positively charged amino acid blocks with changes to our internal clocks.

Summary: Research by a team from Rensselaer Polytechnic Institute, led by Jennifer Hurley, PhD, uncovered complex interactions between the disordered clock protein FRQ and the protein FRH in the fungus Neurospora crassa, which were found to influence the circadian clock’s ability to maintain continuous rhythms without needing daily resets by light. The study highlights the broader implications of circadian clock disruptions in humans, which are linked to higher rates of diseases such as cancer and autoimmune disorders. 

Key Takeaways:

  • The study discovered that the disordered clock protein FRQ interacts with the protein FRH in a more complex manner than previously thought, involving multiple positively charged regions.
  • These protein interactions help the circadian clock maintain continuous rhythms, which are essential for regulating behaviors and physiological processes without the need for daily light resets.
  • Understanding these mechanisms opens the door to practical applications, including optimized chronotherapy for medical treatments, better management of jet lag and shift work, and advancements in biofuel production.

Circadian clocks, which drive circadian rhythms, are entwined with many essential systems in living things including plants, fungi, insects, and even humans. Because of this, disruptions to our circadian clocks are linked to higher disease rates in humans, including certain cancers and autoimmune diseases. 

“As proteins are the building blocks of life, it’s important to gain a fundamental understanding of how these proteins work together,” says Rensselaer Polytechnic Institute’s Jennifer Hurley, PhD, Richard Baruch M.D. Career Development Chair and associate department head of biological sciences, in a release. “Knowing how proteins interact can teach us how an organism will behave, and can also give us the opportunity to alter that behavior.” 

Discovering the Bear Hug Interaction

In research published in Nature, Hurley and team discovered that the disordered clock protein FRQ, in a fungus called Neurospora crassa, interacted with a protein called FRH in an unexpected way. They found regions or “blocks” on FRQ that were positively charged. These blocks allowed FRQ and FRH to interact across many different regions.

“While proteins are often thought of as having a well-ordered shape, there is a whole class of proteins that are more flexible, like wet spaghetti noodles,” says Hurley in a release. “This flexibility can be important in proteins interactions. In the case of FRQ, we think that its ‘noodliness’ allows the blocks of positive charge to bond to FRH, perhaps like a bear hug.” 

Implications for Circadian Rhythm Function

She adds in a release, “We expected a simple, straightforward interaction between FRQ and FRH, and we found the interaction was much more complex than we expected.” 

Hurley and team found that this so-called bear hug causes the molecular circadian clock to flip from being an hourglass, which needs to be reset every day by light, to a persistent oscillator, which allows for a continuous rhythm without needing to be reset by light. This persistent circadian oscillator is the fundamental way in which the circadian clock keeps time, regulating anything from our behaviors to how an animal in the Arctic knows when to hunt, even when there is no light available in the winter months.

Broader Implications and Future Applications

Each new insight into the mechanisms of our circadian clocks brings us closer to being able to make alterations for great practical benefit. If we could manipulate the circadian clock, it could help in the production of biofuels, in combating jet lag, and in ensuring the health of shift workers and others with irregular schedules.

Health care offers vast opportunities to apply our knowledge of circadian rhythms. “Our field refers to this as ‘chronotherapy,’” says Hurley in a release. “If you get injured at one time of day, you heal much faster than at another. Therefore, we can schedule surgeries at the right time of day. We can even time chemotherapy treatments to when healthy cells are not dividing but cancer cells are, lessening side effects and increasing treatment efficacy.” 

Curt Breneman, PhD, dean of Rensselaer’s School of Science, adds in a release, “With this research, professor Hurley and her team have, once again, advanced our understanding of how circadian rhythms work on a molecular level. This kind of in-depth understanding of the mechanisms of circadian processes opens the door to better mitigation of their effects in higher organisms and humans.”

Photo caption: Jennifer Hurley, PhD

Photo credit: Rensselaer Polytechnic Institute