New computational process could help condense decades of disease biology research into days

(Press-News.org)

At 10 one-millionths of a meter wide, a single human cell is tiny. But something even smaller exerts an enormous influence on everything a cell does: proton concentration, or pH. On the microscopic level, pH-dependent structures regulate cell movement and division. Altered pH response can accelerate the development of cancers and neurodegenerative diseases such as Alzheimer’s and Huntington’s.

Researchers hope that pinpointing pH-sensitive structures in proteins would help them determine how proteins respond to pH changes in normal and diseased cells alike and, ultimately, to design drugs to treat these diseases.

Now, in a new study out today in Science Signaling, researchers at the University of Notre Dame present a computational process that can scan hundreds of proteins in a few days, screening for pH-sensitive protein structures.

“Before even picking up a pipette or running a single experiment, we can predict which proteins are sensitive to these pH changes, which proteins actually drive these critical processes like division, migration, cancer development and neurodegenerative disease development,” said Katharine White, the Clare Boothe Luce Assistant Professor in the Department of Chemistry and Biochemistry. “No more searching for the needle in the haystack.”

Determining exactly how pH changes affect the behavior-driving proteins on a molecular level has been a challenge because researchers must laboriously test individual proteins in a signaling pathway for pH sensitivity one by one. Across biology, only 70 cytoplasmic proteins have been confirmed as pH-sensitive — though researchers hypothesize that there are many, many more — and of those, the molecular mechanisms of only 20 are known.

The new study, supported by funding from the National Science Foundation and the National Institutes of Health, developed and validated a modular, computational pipeline that predicts the location of pH-sensitive structures based on existing structural and experimental data.

In the process of developing the pipeline, White’s research group predicted and validated the pH sensitivity of a distinctive binding module known as the Src homology 2 (SH2) domain, which appears in proteins crucial for cell signaling, immune response and development, as well as the pH-dependent function of c-Src, an intensively studied enzyme that is activated in many cancers.

“These proteins are central to cell regulation in addition to being mutated in certain cancers, and in addition to showing that they are pH-sensitive, we’ve also found exactly where on the protein the pH regulation is occurring,” explained Papa Kobina Van Dyck, the lead study author and a recent doctoral graduate in biophysics. “We’ve managed to condense 25 years of work into a few weeks.”

“In addition to cancer and neurodegeneration, pH dynamics are associated with diabetes, autoimmune disorders and traumatic brain injury,” White said. “Our pipeline is a powerful tool for understanding and, ultimately, designing treatments for these conditions, with the potential to transform the field.”

To read the complete news story, visit research.nd.edu.

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