Glycosaminoglycans activate peptidylarginine deiminase 4 by enhancing calcium affinity
Abstract
Rheumatoid arthritis is a chronic inflammatory disease driven by abnormal protein modifications. These include citrullination of arginine residues by the calcium-activated enzyme peptidylarginine deiminase 4 (PAD4). However, calcium in body fluids may not fully activate PAD4, suggesting the potential involvement of other activators. In this study, we investigated the ability of glycosaminoglycans (a class of negatively charged polysaccharides) to modulate PAD4 activity. We found that model glycosaminoglycans bind to the enzyme with a nanomolar affinity, increase its calcium sensitivity, and require enzyme dimerization for activation. These effects depend on the size and negative charge of the glycosaminoglycan, and its various natural forms activate PAD4. Thus, our findings elucidate a mechanism by which common physiological compounds modulate PAD4 activity, potentially contributing to disease etiology.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (15)
Grzegorz P. Bereta
Malopolska Centre of Biotechnology, Jagiellonian University
Ewa Bielecka
Karolina Marzec
Malopolska Centre of Biotechnology, Jagiellonian University
Łukasz Pijanowski
Malopolska Centre of Biotechnology, Jagiellonian University
Artur P. Biela
Malopolska Centre of Biotechnology, Jagiellonian University
Piotr Wilk
Malopolska Centre of Biotechnology, Jagiellonian University
Marta Kamińska
Broegelmann Research Laboratory, University of Bergen
Jakub Nowak
Elżbieta Wątor-Wilk
Malopolska Centre of Biotechnology, Jagiellonian University
Przemysław Grudnik
Dominik Kowalczyk
Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University
Joanna Kozieł
Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University
Piotr Mydel
Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University
Marcin Poręba
Department of Chemical Biology and Bioimaging, Faculty of Chemistry, Wroclaw University of Science and Technology
Tomasz Kantyka