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Uncovering a key to protein stability

Of the hundreds, sometimes thousands, of amino acid building blocks that make up each protein, one type is crucial for stability and folding: methionine. It is readily oxidized by reactive oxygen species, and oxidation can destabilize proteins. Methionine oxidation can be necessary for proper protein folding and cellular function, but it also can cause defects during aging and contribute to neurological disorders such as Alzheimer’s disease.

Researchers have observed that methionine oxidation plays a key role in protein destabilization but previously did not know which methionines must be oxidized to disrupt protein folding. Ethan J.C. Walker and a team at the University of Rochester were the first to show that methionine oxidation of residues buried deep within a protein drive folding disruption.    

In this study, Walker used the E. coli proteome and a method called SPROX: stability of proteins through rates of oxidation. SPROX allowed the team to harness mass spectrometry to look at thousands of proteins at once, which rapidly accelerated their research.

After studying theoretical protein stability, Walker turned to another application of SPROX. The team examined how buried methionines are important for the stability of thermophiles, microorganisms that live in extremely high temperatures.

“Ever since I found out that some bacteria could basically live in boiling saltwater, I’ve been fascinated,” Walker said.

Specifically, Walker scrutinized Thermus thermophilus, a species of bacteria with an optimal growth temperature of 149 F that was found in a Japanese hot spring. The group showed that, compared to E. coli, the thermophile’s proteome is more resistant to methionine oxidation and is fine-tuned to exist at high temperatures. Thermophiles tend to use fewer methionine amino acids, which may be an adaptation to avoid protein unfolding.

Walker’s work helped open up a whole new area of research on methionine in the Ghaemmaghami lab. In the future, the project will focus more on methionine’s role in protein stability and folding.

“Methionine started out as a tool,” Walker said, “but then became so much more important and interesting to the project in its own right.”

was published in the Journal of Biological Chemistry in May 2022. Walker and other winners of the JBC Tabor Award will give talks during a symposium on Sunday, March 26, at Discover BMB in Seattle.