Notre Dame posts protein pH pipeline

University of Notre Dame researchers said on September 7 that a computational pipeline highlighted in an X post can scan hundreds of proteins in a few days to predict which parts of those proteins respond to pH changes. The post points to work from Katharine White’s lab that was later described by Notre Dame in a November 11, 2025 university release and published in *Science Signaling*. Notre Dame said the method identified pH-sensitive structural networks in SHP2 and Src, two signaling proteins tied to cancer biology. The researchers said the goal is to narrow the search for protein sites that could be targeted experimentally and, eventually, in drug discovery. ### What exactly did the Notre Dame team say it built? Notre Dame said the group developed a “modular, computational pipeline” that predicts the location of pH-sensitive structures using existing structural and experimental data. In the university’s 2025 release, White said the approach lets researchers predict which proteins are sensitive to pH changes before running lab experiments. (news.nd.edu) The *Science Signaling* paper described the same system as a pipeline to identify pH-sensitive proteins and their mechanisms. The paper said intracellular pH dynamics regulate normal cell biology, but that only a small number of pH-dependent proteins and mechanisms had been identified previously. ### Why are pH changes inside cells important here? The Notre Dame release said pH-dependent structures regulate cell movement and division, and that altered pH response can accelerate the development of cancers and neurodegenerative diseases including Alzheimer’s and Huntington’s. (news.nd.edu) White said researchers want to pinpoint pH-sensitive structures to understand how proteins respond in normal and diseased cells and to support drug design. (science.org) The paper said ionizable residues can gain or lose protons, changing charge states and, in some cases, changing protein behavior across the physiological pH range. That is the basis for looking for pH-sensitive “switches” or residue networks inside signaling proteins. ### Why did SHP2 and Src stand out? The *Science Signaling* study said the pipeline was applied to SHP2, which it described as a pH-sensitive signaling protein with an unknown mechanism. (news.nd.edu) The authors reported that SHP2 phosphatase activity was pH-sensitive in vitro and in cells, and that mutating His116 and Glu252 abolished that pH-sensitive function. The same paper said Src was identified as “an unrecognized pH-dependent kinase” and that mutation of the identified ionizable network abolished pH-sensitive activity. (biorxiv.org) Notre Dame’s release said the group predicted and validated pH sensitivity in the SH2 domain and in c-Src, which it described as an enzyme activated in many cancers. ### What do the researchers mean by structural “switches”? (biorxiv.org) The paper said constant-pH molecular dynamics simulations supported an allosteric mechanism in which pH-dependent binding of inhibitory SH2 domains regulates the catalytic domains of SHP2 and Src. In practical terms, the researchers were pointing to clusters of ionizable residues whose protonation state can change with pH and alter how parts of the protein interact. (biorxiv.org) Papa Kobina Van Dyck, the lead author, said in Notre Dame’s release that the team had found “exactly where on the protein the pH regulation is occurring.” That comment matched the paper’s focus on mapped residue networks rather than only broad protein-level sensitivity. ### How much faster is this than older approaches? Notre Dame said the pipeline can scan hundreds of proteins in a few days, compared with the slower process of testing proteins one by one in signaling pathways. (science.org) The university release said only 70 cytoplasmic proteins had been confirmed as pH-sensitive across biology, and the molecular mechanisms were known for only 20 of them. (news.nd.edu) The release framed the pipeline as a way to reduce that bottleneck. White said the method could identify candidate proteins before researchers “pick up a pipette,” while the paper said the team also found conserved putative pH-sensing networks across other SH2-domain signaling proteins. ### Where does the work go from here? The November 11, 2025 Notre Dame release said the study was supported by the National Science Foundation and the National Institutes of Health. (news.nd.edu) The published paper lists Papa Kobina Van Dyck as lead author and Katharine A. White as corresponding author, and it reports that the pipeline identified putative pH-sensing networks across SH2-domain-containing signaling proteins beyond SHP2 and Src. The next concrete step is in the paper itself: testing those predicted networks experimentally in additional proteins. Notre Dame’s release said the approach is meant to guide future work on proteins involved in cell signaling, immune response and development, with White’s lab positioning the pipeline as a screening tool for follow-up validation. (news.nd.edu)