Using advanced microscopy, researchers have visualized two key protein structures in the human body for the first time—a breakthrough that could pave the way for more effective treatments, aided by technology at the University of Cincinnati’s Center for Advanced Structural Biology.

A team of structural biologists at the University of Cincinnati, led by Tom Seegar, PhD, has for the first time visualized the atomic structures of two protein complexes involved in inflammation. Published in PNAS, this study reveals how these proteins interact and regulate inflammatory signaling. First authors Joe Maciag, PhD, and graduate student Conner Slone contributed to uncovering how the enzyme’s structure controls its function. “If you can see something, you can figure out how it works,” said Seegar.

Figure 1. High-Res Immune Protein Structures Unlock New Therapy Paths

Visualizing the Proteins

Using advanced cryogenic electron microscopy, the Seegar Lab revealed the structure of the ADAM17 enzyme bound to its regulator protein iRhom2, uncovering crucial features that control its activity. They identified the key interaction within the ADAM17-iRhom2 complex that directs how protein substrates are processed. Figure 1 shows High-Res Immune Protein Structures Unlock New Therapy Paths.

ADAM17 is a vital enzyme present in all cells, essential for development and immune regulation. Its dysregulation is associated with chronic inflammatory diseases and conditions including rheumatoid arthritis, cancer, and Covid-19.

Researchers are now investigating how ADAM17 interacts with other proteins involved in immune response and tissue repair. “In cancers and rheumatoid arthritis, excessive signaling occurs,” said Maciag, “but current treatments often cause side effects worse than the disease.”

The team is focusing on targeting iRhom2 for more precise therapies. They have identified a key structural feature inside the cell—the “re-entry loop” of iRhom2—that transmits signals from the cell’s interior to its exterior, crucial for ADAM17’s function outside the cell and previously poorly understood.

Seegar highlighted the significance: “This work lays the groundwork for developing therapies aimed at ADAM17-related diseases, opening new paths to treat critical health issues.”

New Research Hub Established

The ADAM17-iRhom2 Complex represents the first protein structures revealed by UC’s Center for Advanced Structural Biology, launched in 2022.

Seegar expressed gratitude for the center, highlighting its crucial role as a research core facility enabling this work. The center’s state-of-the-art cryogenic electron microscopy (cryo-EM) technology, centered on its transmission electron microscope (TEM), allows researchers to visualize complex proteins without leaving campus.

Maciag emphasized the privilege of having this equipment in-house, noting its importance for advancing cellular biology and deepening understanding of inflammation in diseases.

The Seegar Lab also utilized UC’s Advanced Research Computing Center (ARC) for on-campus data processing, which helped build a detailed 3D model of the ADAM17-iRhom2 Complex.

Looking ahead, the team plans to focus on further studying iRhom2, with Slone noting that these adapter proteins are poorly understood [1]. Their goal is to gain specificity in controlling them, which could open new avenues for managing disease states.

References:

1. https://scitechdaily.com/scientists-finally-see-key-protein-that-controls-inflammation/

Cite this article:

Janani R (2025), Scientists Visualize Crucial Inflammation-Regulating Protein for the First Time, AnaTechMaz, pp. 440