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.
News
Swiss laboratory uses old drugs against rare diseases
Researchers at the University of Geneva are combing through collections of approved drugs to find new therapies for rare diseases – with some success. This approach is gaining traction around the world, while pharmaceutical [...]
Nanozyme Aptasensors Show Promise for Faster Food, Health, and Environmental Testing
By pairing robust artificial enzymes with highly selective aptamers, nanozyme aptasensors could help detect disease biomarkers, pathogens, and contaminants faster, but the review shows that real-world deployment still depends on overcoming matrix interference, biofouling, [...]
Paralyzed Man Feels Sensation Again With Brain Stimulation Device
Aneuroprosthetic system has allowed a man with paralysis to grasp and lift objects and feel touch again. The device helped 42-year-old Keith Thomas of Massapequa, New York, who was paralyzed from the chest down [...]
Global Cancer Cases Could Surge 67% by 2050, New Report Warns
New data reveal major geographic disparities and highlight the urgent need for global action on prevention, early detection, and equitable access to treatment. For roughly one in five people worldwide, cancer will become part [...]
A Deadly Ebola-Like Virus Is Spreading. Are We Ready?
BU virologist Nancy Sullivan says the Bundibugyo outbreak in the Democratic Republic of the Congo underscores the need for broader outbreak preparedness. The death of a nurse marked the moment health officials recognized that [...]
Why Most Animal Viruses Never Become Human Pandemics
From receptor mismatch to risky human-animal interfaces, this article explains why spillover is common but true pandemic emergence remains rare. Introduction Humans are constantly exposed to animal viruses through farming, wildlife contact, and the [...]
Stem cell organoids repair heart microvessels in coronary artery disease models
A Stanford University team has shown that vascular organoids derived from human stem cells can repair the heart’s microvessel network in pigs with ischaemic heart disease – a proof-of-concept advancement that could open new therapeutic [...]
Goodbye GP waiting rooms, hello prevention at home
Prevention is suddenly everywhere in NHS reform. The recent £340m community pharmacy deal is moving more services onto the high street. Community Diagnostic Centres are being expanded, and the Neighbourhood Health Framework sets out [...]
Ebola control is weakened by mistrust and cultural insensitivity
Effective response depends on cooperation with communities and frontline workers, writes Zaeem ul Haq The current Bundibugyo Ebola outbreak in the Democratic Republic of the Congo (DRC) and Uganda is exposing dangerous gaps in [...]
Building the Brain Requires Millions of Dangerous DNA Breaks
Scientists discovered that building a healthy brain involves an unexpected step: young neurons routinely break and rapidly repair their own DNA. As the brain develops, newly formed nerve cells must travel through tightly packed tissue [...]
One Tiny Change May Explain How Viruses Jump From Bats to Humans
Scientists found that one tiny genetic change may determine whether a bat virus stays in bats or becomes a human threat. Most infectious disease outbreaks begin when a virus or other pathogen crosses from animals into [...]
Scientists Discover 250+ Genes That Could Lead to New Ways To Prevent Melanoma
The world’s largest study of mole genetics identified hundreds of genes tied to melanoma risk, uncovering potential new drug targets and paving the way for more accurate melanoma screening and prevention. Researchers at QIMR [...]
Breakthrough Diabetes Treatment Reprograms the Immune System
An engineered stem cell therapy reversed new-onset Type 1 diabetes in mice by shifting the immune system away from attacking insulin-producing cells. For more than a century, people with Type 1 diabetes have relied [...]
Taking the world’s temperature: WHO chief spotlights global health emergencies
Taking the world’s temperature on pressing health matters, WHO Director-General Tedros Adhanom Ghebreyesus provided the latest on current global challenges - and successes when it comes to international cooperation. “The outbreaks of hantavirus, Ebola and Marburg all show [...]
Scientists Create Tiny “Mini Livers” That Could One Day Replace Liver Transplants
Engineered tissue grafts could help perform key liver functions and benefit thousands of people living with liver failure. The liver is one of the body’s hardest-working organs, carrying out hundreds of vital jobs, from [...]
NanoMedical Brain/Cloud Interface – Explorations and Implications. A new book from Frank Boehm
New book from Frank Boehm, NanoappsMedical Inc Founder: This book explores the future hypothetical possibility that the cerebral cortex of the human brain might be seamlessly, safely, and securely connected with the Cloud via [...]
