What is it about?
We have tested how glycosaminoglycans (GAGs)—negatively charged sugar chains—affect the enzyme PAD4, which converts arginine to citrulline in proteins. They measured enzyme activity, binding, and calcium dependence using purified PAD4 and different GAGs such as heparin and chondroitin sulfate. Experiments showed that GAGs bind to PAD4 and increase its activity by enhancing its ability to use calcium effectively.
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Why is it important?
Rheumatoid arthritis is a disease in which the body’s immune system mistakenly attacks its own tissues. People with this condition often have antibodies that recognize proteins containing a modified form of the amino acid arginine, called citrulline. Scientists are still trying to understand what causes these modified proteins to form and what triggers the disease to start. One path is modification by PAD4, a citrulline-forming enzyme. In our study, we found that certain sugar-like molecules called glycosaminoglycans—such as heparin, heparan sulfate, and chondroitin sulfate—can make an enzyme called peptidylarginine deiminase 4 (PAD4) more active. This enzyme normally needs calcium to work, but calcium levels in the body are usually too low to fully activate it. Glycosaminoglycans seem to help PAD4 work better even at normal calcium levels. Because these molecules are common in joints, they might increase the formation of citrullinated proteins there, potentially triggering or maintaining the immune response seen in rheumatoid arthritis.
Perspectives
This research was both a challenge and a joy. This work represents years of curiosity about how PAD4 really works inside the body, and the excitement of finally finding one of the missing pieces of the puzzle. Discovering that glycosaminoglycans can naturally activate PAD4 was one of those moments when everything suddenly makes sense. It was then followed by numerous techniques and experiments to make our story convincing. Did everything work as planned? No, it never does. But it was a great journey nonetheless! I truly hope You will find this story as inspirational example, where work and persistence may elevate basic science research and put the findings on a path to potential translation.
Tomasz Kantyka
Uniwersytet Jagiellonski w Krakowie
Read the Original
This page is a summary of: Glycosaminoglycans activate peptidylarginine deiminase 4 by enhancing calcium affinity, Proceedings of the National Academy of Sciences, October 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2508369122.
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