University of Cincinnati structural biologists have become the first researchers worldwide to visualize iRhom1, a regulator protein, bound to the ADAM17 enzyme. The Seegar Lab achieved this breakthrough using cryogenic electron microscopy at UC's Center for Advanced Structural Biology facility.
The achievement reveals how iRhom1 controls ADAM17, an enzyme involved in cell surface protein shedding, a process critical for cell signaling and immune function. ADAM17 releases proteins from cell membranes, allowing them to function as signaling molecules throughout the body. Without proper regulation, this enzyme contributes to inflammation, cancer progression, and other diseases.
iRhom1 acts as a molecular guardian, governing when and how ADAM17 operates. Understanding their interaction at atomic resolution opens new avenues for drug development targeting diseases where ADAM17 activity spirals out of control, including inflammatory bowel disease, cancer, and rheumatoid arthritis.
Cryogenic electron microscopy, which won the 2017 Nobel Prize in Chemistry, freezes proteins in their native state at temperatures near absolute zero, then images them with electron beams. This technique reveals three-dimensional structures at near-atomic resolution without requiring crystallization, a major advantage over traditional X-ray crystallography.
The Seegar Lab's visualization shows exactly how iRhom1 positions itself relative to ADAM17, identifying contact points and conformational changes that regulate enzyme activity. This structural information provides a blueprint for researchers designing inhibitors that could modulate ADAM17 without completely shutting it down, which would cause harmful side effects.
The research addresses a long-standing gap in structural biology. While scientists understood the proteins individually, seeing them together as a functional complex required technological advances and methodological refinement. The UC team's work demonstrates how modern cryo-EM capabilities can solve previously