Inside the Center for Advanced Structural Biology at the University of Cincinnati, researchers using cryogenic electron microscopy have just peered into one of medicine's longest-standing mysteries—how a single enzyme responds to signals racing across the cell membrane. The Seegar Lab has become the first in the world to visualize iRhom1, a regulatory protein, bound to the ADAM17 enzyme, revealing the precise molecular machinery that has eluded researchers for three decades.
This breakthrough matters because ADAM17 is no minor player in human biology. The enzyme is essential for proper tissue development and immune response, and its dysregulation drives a spectrum of diseases from chronic inflammation and cancer to neurodegenerative disorders. Understanding how iRhom1 and its structural twin, iRhom2, activate ADAM17 opens the door to new treatments for conditions that affect millions. "ADAM17 is rapidly activated in response to changes in intracellular signaling networks, yet how these signals are transmitted across the cell membrane to where ADAM17 resides has remained a long-standing question in the field," said Tom Seegar, an assistant professor in the Department of Molecular and Cellular Biosciences and an Ohio Eminent Scholar.
The research, published in Cell Reports, reveals that iRhom1 and iRhom2 function as molecular relays—transmitting information across the cell surface and linking intracellular signaling to ADAM17 activation. What makes this discovery particularly striking is that the two proteins are structurally identical and respond to intracellular signals in the same way, yet they perform distinctly different functions. "While the structures are remarkably similar, their functions are divergent," explained Joe Maciag, a research scientist and co-first author of the study. "The ability to maintain distinct roles despite having overall structural similarities can most likely be attributed to the nuance of their sequence, which aids in preferentially recognizing and cleaving substrates."
The team, including third-year graduate student Joe Ungvary, went further and examined a real-world case: an iRhom1 mutation found in a patient with cardiomyopathy. The variant was completely defective in supporting iRhom1-ADAM17 function. "We were able to see that iRhom1 proteins were likely not able to fold properly," said Ungvary. "The structure of the protein isn't correct; therefore, its function is null." With iRhom1 unable to do its job, ADAM17 couldn't work properly or reach its target near the cell's surface—explaining the patient's disease.
What makes this particularly significant is that this human case reveals something different from animal models of the same disorder, providing researchers with a clearer window into how iRhom dysfunction actually affects people. "Notably, this phenotype differs from those observed in animal models and may more accurately reflect the consequences of iRhom1 dysfunction in humans," Seegar noted. "This is some of the first understanding of how this biology is different in human and animal models."
The findings position iRhom proteins, particularly iRhom2, as promising new drug targets for chronic inflammatory diseases. With three decades of unanswered questions now beginning to yield to structural biology's most sophisticated tools, Cincinnati's researchers have laid the foundation for a new era of targeted therapeutics—drugs designed to dial down the very molecular relay systems that drive disease.