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Puzzling out science

March 7, 2023

Science is like a jigsaw puzzle, according to Ethan J.C. Walker; some people work on the edge pieces first, whereas others like to categorize the pieces by color. From the time he was a child, Walker has been fascinated with the enigma of science and looking at how millions of tiny details fit into a universal big picture.

Walker is a postdoctoral associate at the Broad Institute studying drug development for prion diseases. Before moving to Massachusetts, he worked as a graduate researcher at the University of Rochester in Sina Ghaemmaghami’s lab. That’s where he developed his love for researching protein stability and folding.

Ethan Walker

“I love seeing the research process unfold and being the first person to discover something,” Walker said.

Working in a lab can be fast-paced and demanding, so Walker believes self-care is one of the keys to success.

“Research is a marathon; not a sprint,” he said. “It may sound dumb, but it’s true. There are times when you do need to sprint like when you have a grant deadline or really need to get a paper out. There are definitely times where it’s busy, busy, busy. But, you also have to make sure that you ultimately take care of yourself because it’s so easy to get wrapped up in the rush.”

Building on the puzzle comparison, Walker further likened the research process to the folding of a complex protein: A scientist begins with thousands of unorganized pieces, and the path to the complete picture is not always clear.

“We are always presented with science as a linear, logical progression,” Walker said. “In reality, it is much messier than that, and during graduate school, I got an appreciation for the chaos that grows out of all the questions.”

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.”

“Protein folding stabilities are a major determinant of oxidation rates for buried methionine residues” 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.