Scientists Finally “See” Key Protein That Controls Inflammation

Researchers used advanced microscopy to uncover important protein structures.

For the first time, two important protein structures in the human body are being visualized, thanks in part to cutting-edge technology at the University of Cincinnati’s Center for Advanced Structural Biology. This breakthrough could lead to the development of more effective therapeutics.

The research, conducted by a team of structural biologists at UC, was published in the Proceedings of the National Academy of Sciences (PNAS).

This is the first publication from the Seegar Lab at UC. Tom Seegar, PhD, Ohio Eminent Scholar and assistant professor in the Department of Molecular and Cellular Biosciences in the College of Medicine, is the corresponding author.

The study’s first authors are Joe Maciag, PhD, a research scientist in the Seegar Lab, and Conner Slone, a graduate student assistant in the same lab.

For the first time, they are visualizing the physical, atomic structure of two protein complexes, observing how they interact, how their functions change, and how this process drives inflammatory signaling.

“If you can see something, you can figure out how it works,” said Seegar. “We are figuring out what this enzyme looks like and how it’s regulated.”

What they saw

The Seegar Lab used advanced cryogenic electron microscopy to reveal the structure of the ADAM17 enzyme bound to its regulator protein, iRhom2, and identified key features essential for its activity. They also pinpointed the critical interaction within the ADAM17-iRhom2 complex that governs how protein substrates are processed.

Scientists have long known that ADAM17 is a vital enzyme found in all cells, playing a key role in development and immune system regulation. It becomes dysregulated in chronic inflammatory diseases and has been linked to conditions such as rheumatoid arthritis, cancer, and Covid-19.

Researchers are now studying how ADAM17 communicates with other proteins involved in immune response and tissue repair. “We know in some cancers and rheumatoid arthritis, way too much signaling is occurring,” said Maciag. “But some treatments create too many side effects, worse than the disease itself.”

Maciag explained that the team is exploring ways to target iRhom2 for more precise therapeutic approaches. They have already identified structural features inside the cell, called the “re-entry loop” of iRhom2, that transmit information from the cell’s interior to its exterior. These structures are essential for ADAM17 to function outside the cell and had not been well understood until now.

Seegar emphasized the human impact. “This work provides a foundation for designing therapies targeting ADAM17-related diseases, offering new strategies to address critical health conditions,” he said.

New research core facility

The ADAM17-iRhom2 Complex contains the first protein structures coming out of UC’s Center for Advanced Structural Biology, established in 2022.

“We are indebted to UC,” said Seegar. “Our work wouldn’t be possible without this research core facility.”

The cryogenic electron microscopy technology being used has transformed structural biology. The center’s focal point is its transmission electron microscope (TEM), which is ideally suited for screening cryo-EM samples and allows researchers to see complex proteins without leaving UC’s campus.

“It’s a privilege to have this microscope in house, and it’s exciting to use it to solve these structures,” said Maciag. “It’s important to our field of cellular biology and will help drive research forward and how we approach our understanding of inflammation in known disease states.”

The Seegar Lab used UC’s Advanced Research Computing Center (ARC) for data processing, allowing them to keep their data, used to create a 3D model of the ADAM17-iRhom2 Complex, on campus as well.

Moving forward, Seegar’s lab plans to research iRhom2 more closely.

“These adapter proteins are not well understood,” said Slone. “Our research will be in understanding them and will be driven by specificity. Ideally, controlling these will allow researchers to control disease states.”

Reference: “Structural insights into the activation and inhibition of the ADAM17–iRhom2 complex” by Joseph J. Maciag, Conner E. Slone, Hala F. Alnajjar, Maria F. Rich, Bryce Guion, Igal Ifergan, Carl P. Blobel and Tom C. M. Seegar, 13 June 2025, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2500732122

The study was funded by the National Institute of General Medicine Sciences and with support from a University of Cincinnati Research Innovation/Pilot Grant.