Scientists visualize a key cell protein regulating inflammatory disease pathways
· News-MedicalTom Seegar, PhD, corresponding author, assistant professor, Department of Molecular and Cellular Biosciences and an Ohio Eminent ScholarADAM17 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."
The Seegar Lab also revealed new insights into why the iRhom1 and iRhom2 proteins are considered master regulators of ADAM17, which exists only in a complex with iRhom1 and iRhom2. They found that the structures of both iRhom1 and iRhom2 are identical, as are their responses to intracellular signals, leading to a unified model for enzyme activation.
How they know which function or job to do is unknown, and why they make different decisions is expected to be studied more closely in the future. "It's what's been missing in our field for 30 years," said Seegar.
In addition, the iRhom proteins, particularly iRhom2, will further serve as a novel drug target for treating chronic inflammatory diseases, as they appear to be the drivers of ADAM17 specificity.
Researchers also examined an iRhom1 mutation identified in a patient with cardiomyopathy.
They found 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."
In this case, ADAM17 could neither work properly nor reach its target near the cell's surface. Dysregulated ADAM17 activity has been implicated in a wide spectrum of diseases such as chronic inflammation, cancer and neurodegenerative disorders.
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