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Timing is everything for key protein

All proteins — the complicated biochemical entities that carry out the basic processes of life — are made in the same way. Inside living cells, tiny molecular machines known as ribosomes read messenger RNA, turning the genetic code into long sequences of amino acids. Then these sequences “fold” — arrange themselves — into the three-dimensional shapes of finished proteins.

The relationship between these processes of RNA reading and protein folding is at the center of paper recently published in the journal Nature on circadian rhythms, the roughly 24-hour cycles that regulate the lives of almost all organisms. University of Texas Medical Branch at Galveston researchers played a key role in the project that produced the paper, which was led by a team from the University of Texas Southwestern Medical Center and also involved scientists from Texas A&M University and China’s National Institute of Biological Sciences.

The paper, titled “Non-optimal codon usage affects expression, structure and function of clock protein FRQ,” examines the connection between the rate at which a protein dubbed FREQUENCY is produced and its function in a timekeeping mechanism used by a wide variety of living things. The experiments conducted for this research used a fungus called Neurospora crassa, but FREQUENCY also governs circadian rhythms in animals, including human beings.

The investigation started from the observation that FREQUENCY is synthesized more slowly than most other proteins that make up Neurospora, a type of bread mould often used as a model organism by researchers. The scientists wanted to know whether this slow pace was essential to FREQUENCY’s function, so they artificially sped up the process by which the fungus’ ribosomes read messenger RNA.

This acceleration process depended on a quirk in the RNA translation process involving RNA codons, the individual units that correspond to each amino acid. Particular amino acids can be coded for by more than one codon, and some codons are read more quickly than others. Thus, it’s possible to produce the same amino acid sequence from different sets of codons read at different speeds.

“We inserted a codon sequence into the fungus that was optimized to be translated faster,” said UTMB associate professor José Barral. “We found that more of the protein was made, which is consistent with a faster translation rate — but we also saw that the organism’s circadian rhythm goes completely out of whack.”

After performing another series of experiments, the researchers determined that the extra FREQUENCY wasn’t the issue. The real problem was that much of the protein had an improper structure — a result of the speed with which it had been produced.

“What happens is the protein doesn’t fold properly when it’s made fast,” Barral said. “We’ve made this happen before by inserting new genes into bacteria, but the great thing here is that, like human beings, these fungi are eukaryotes — they’re much more complex than bacteria. Also, this is an endogenous protein, something that’s naturally part of the organism, and it performs an important biological function.”

The senior and lead authors of this paper were UT Southwestern’s Yi Liu and Mian Zhou. Other paper authors include Jinhu Guo, Michael Chae and Joonseok Cha of UT Southwestern, She Chen of China’s National Institute of Biological Sciences and Matthew Sachs of Texas A&M. This research was supported by funding from the National Institutes of Health and the Welch Foundation.

The University of Texas Medical Branch.

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