Proteins can tune their folding to circadian rhythms

Proteins are central to biology. For the most part, proteins in the body are crucial for catalyzing reactions that carry out almost all of our biologial processes. For a protein to be useful, after it’s made by a ribosome, it needs to fold into a 3-dimensional structure that is unique to its sequence.

Its been widely thought that every unique sequence corresponds to a single unique structure. However, in biology, there are always exceptions to the rule. Now Yong-Gang Chang and colleagues report in a recent article in Science that a protein responsible for timing the internal circadian clock has two distinct folds for the same sequence, and that both of these folds are crucial for its functioning! [1]

The researchers study the circadian clock of cyanobacteria. This internal clock is quite simple as it only requires three proteins to function by itself. These three proteins have roles in activating and repressing one another at time intervals that follow the Earth’s night-day cycle. These proteins are also capable of interacting with other proteins to cascade events to control time-specific biological functions in the cyanobacteria.

The researchers found that one of the proteins can adopt a very different fold when it is bound to one of other clock proteins compared to when it is unbound or “free.” In this fold-switched state, the protein flips an alpha-helix into a beta-strand and flips a different beta-strand turns into a new alpha-helix! The researchers theorized that they could tune the switching behavior by making specific mutations that could make the protein switch more often, or switch irreversibly.

This study shows that the ability to fold-switch and the speed of fold-switching is very important for regulating the circadian rhythms in the organisms studied. When mutated proteins that had messed-up switching were put into cells, it caused the cells to elongate without dividing and totally screwed up the phosphorylation cycles. Protein dynamics may be much more subtle and important than previously though, and clearly an amino acid sequence does not absolutely determine its structure.

Anyone who studies proteins should care, because this report tells us that protein structures are more malleable than previously thought and, though subtle, the differences can be quite important for a healthy functioning biological organism.

A lot of studies on proteins focus on crystallography which essentially “locks” in a conformational state. However, we may have been missing out on a lot of important conformation states if other proteins out there also have this “metamorphic” behavior using these techniques. [2] New techniques may be needed to unlock more of these interesting proteins!

References

1. Chang, Yong-Gang, et al. “A protein fold switch joins the circadian oscillator to clock output in cyanobacteria.” Science (2015): 1260031.
2. Murzin, Alexey G. “Metamorphic proteins.” Science 320.5884 (2008): 1725.