It's what's been missing in our field for 30 years
At the University of Cincinnati, a team of molecular scientists has done what three decades of inquiry could not: they have rendered visible the precise moment a cell decides to speak. By capturing the first image of the iRhom1 protein bound to the ADAM17 enzyme, they have answered how internal signals cross the membrane and ignite inflammatory processes — a discovery that reframes both the origins of chronic disease and the possibilities for treating it.
- For thirty years, a critical gap in biology persisted: researchers knew intracellular signals activated ADAM17, but the mechanism was invisible — until now.
- When ADAM17 misfires, the consequences cascade across the body, driving chronic inflammation, cancer, and neurodegeneration in ways medicine has struggled to interrupt at the source.
- Using cryogenic electron microscopy, the UC team froze the iRhom1-ADAM17 complex mid-interaction, producing the first structural map of how these two proteins physically communicate across the cell membrane.
- A human mutation in iRhom1 linked to cardiomyopathy behaved differently than animal models predicted — a warning that the biology of iRhom dysfunction may not translate cleanly from lab to clinic.
- iRhom proteins, especially iRhom2, now stand as precise drug targets: because they govern which proteins ADAM17 cleaves and when, blocking them offers more surgical control than targeting the enzyme directly.
A University of Cincinnati research team has resolved a thirty-year mystery in cell biology, mapping for the first time the physical structure of the iRhom1 protein locked in complex with the enzyme ADAM17. Published in Cell Reports, the work answers a foundational question: how do signals originating inside a cell reach an enzyme waiting at its surface?
ADAM17 performs a vital and consequential task — it cleaves proteins from the cell surface in a process called ectodomain shedding, reshaping how cells communicate with one another. Essential to immune response and tissue development, it is equally implicated in chronic inflammation, cancer, and neurodegenerative disease when dysregulated. Tom Seegar's lab used cryo-EM to capture the iRhom1-ADAM17 interaction in structural detail, building on earlier work that had mapped ADAM17 with its related partner, iRhom2. Together, these proteins emerge as molecular relays — transmitting signals across the membrane and directly activating the enzyme.
A striking puzzle surfaced in the data: iRhom1 and iRhom2 are structurally nearly identical and respond to intracellular signals the same way, yet they perform distinct biological functions. Subtle differences in their genetic sequences appear to determine which target proteins each one directs ADAM17 to cleave — a question of how structural sameness produces functional difference that the field will be working to answer for years.
The team also studied a patient-derived mutation in iRhom1 associated with cardiomyopathy. The variant protein could not fold correctly, leaving ADAM17 unable to function or reach the cell surface. Crucially, the disease pattern this produced in humans differed from what animal models of the same defect had shown — a finding that complicates the translation of laboratory discoveries into clinical medicine.
The structural blueprints now in hand point directly toward drug development. Because iRhom proteins govern the specificity of ADAM17 — controlling what it cuts and when — they represent a more targeted intervention point than the enzyme itself. The maps have been drawn; the work of converting structure into therapy has begun.
A team at the University of Cincinnati has accomplished something the field has been chasing for three decades: they've mapped how a single protein tells an enzyme to wake up and start its work. The achievement, published in Cell Reports, answers a fundamental question about how cells communicate with themselves—and it opens a new door for treating chronic inflammatory diseases.
The story centers on two proteins: ADAM17, an enzyme that sits on the surface of cells, and iRhom1, a regulator that controls when ADAM17 springs into action. Tom Seegar's lab at UC's College of Medicine used cryogenic electron microscopy to capture the first-ever image of these two proteins locked together. The visualization revealed the physical structure of iRhom1 bound to ADAM17, showing exactly how information travels from inside the cell to the enzyme waiting at the cell's edge. This builds on the lab's earlier work, published last year, which had mapped the structure of ADAM17 bound to a related protein, iRhom2.
Why does this matter? ADAM17 performs a critical job in the body. It rapidly cleaves proteins from the cell surface—a process called ectodomain shedding—which fundamentally changes how cells talk to one another. This enzyme is essential for proper tissue development and immune response. But when ADAM17 goes haywire, it contributes to a long list of diseases: chronic inflammation, cancer, neurodegenerative disorders. For decades, researchers understood that intracellular signals somehow triggered ADAM17 to activate, but the mechanism remained invisible. How did the signal cross the cell membrane? How did it reach the enzyme? The new structure provides the answer: iRhom1 and iRhom2 act as molecular relays, transmitting information across the membrane and linking internal signaling networks directly to ADAM17 activation.
The research revealed something unexpected. iRhom1 and iRhom2 have nearly identical structures and respond to intracellular signals in the same way. Yet they perform different functions in the body. Joe Maciag, a research scientist in the lab and co-first author of the study, explained that despite their structural similarity, the subtle differences in their genetic sequences allow them to recognize and cleave different target proteins. How these two proteins make different functional choices despite their structural sameness remains an open question—one the field expects to pursue in coming years.
The team also examined a mutation in iRhom1 found in a patient with cardiomyopathy. The variant was completely non-functional. Joe Ungvary, a third-year graduate student and co-first author, found that the mutated protein could not fold properly, rendering it unable to support ADAM17 function. As a result, ADAM17 could neither work correctly nor reach its target location on the cell surface. What made this finding significant was that the human mutation produced a different disease pattern than what researchers had observed in animal models of the same defect. This suggests that the underlying biology of iRhom dysfunction may operate differently in humans than in laboratory animals—a distinction that could reshape how researchers think about translating findings from bench to bedside.
The implications for drug development are immediate. iRhom proteins, particularly iRhom2, now emerge as novel targets for treating chronic inflammatory diseases. Because these regulators control ADAM17's specificity—determining which proteins it cleaves and when—they represent a more precise intervention point than targeting ADAM17 itself. The structural maps provide the blueprint. What remains is the work of turning structure into medicine.
Citações Notáveis
While the structures are remarkably similar, their functions are divergent. 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.— Joe Maciag, research scientist, Seegar Lab
This is some of the first understanding of how this biology is different in humans and animal models.— Tom Seegar, assistant professor and corresponding author
A Conversa do Hearth Outra perspectiva sobre a história
Why did it take thirty years to see how this signal gets transmitted?
Because you need to see the actual three-dimensional shape of the protein complex to understand the mechanism. For decades, researchers knew the signal happened, but they couldn't visualize the physical structure doing the work. Cryo-electron microscopy finally made that possible.
So iRhom1 and iRhom2 look almost identical but do different things. How does that work?
That's the mystery. The structures are remarkably similar, and they respond to the same internal signals the same way. But the subtle differences in their amino acid sequences seem to let them recognize different target proteins. It's like two keys that look almost identical but open different locks.
The patient with the mutation—what does that tell us?
It tells us that when iRhom1 can't fold correctly, ADAM17 is completely stranded. It can't function, can't reach the cell surface. But the disease pattern in that patient was different from what we see in mice with the same mutation. That suggests the biology is genuinely different in humans.
Different how?
We don't fully know yet. But it means animal models might not capture the whole picture of what happens when this protein breaks down in people. That's crucial for drug development.
So iRhom becomes the drug target instead of ADAM17?
Exactly. If you can control iRhom, you control ADAM17's specificity—which proteins it cuts, when it cuts them. That's more precise than just shutting down the enzyme entirely.
What's the next question?
How do iRhom1 and iRhom2 decide which function to perform? Why do they make different choices? That's what the field has been missing.