9HUH

CryoEM structure of human peptidylarginine deiminase type 4 (PAD4) in 10 mM calcium

Summary for 9HUH

• Entry DOI: 10.2210/pdb9huh/pdb
• EMDB information: 52413
• Descriptor: Protein-arginine deiminase type-4, CALCIUM ION (3 entities in total)
• Functional Keywords: pad4, citrullination, calcium, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 151986.28

Authors

Bereta, G.P.,Bielecka, E.,Biela, A.P.,Wilk, P.,Wator-Wilk, E.,Grudnik, P.,Kantyka, T. (deposition date: 2024-12-23, release date: 2025-10-22, Last modification date: 2025-11-12)

Primary citation

Bereta, G.P.,Bielecka, E.,Marzec, K.,Pijanowski, L.,Biela, A.P.,Wilk, P.,Kaminska, M.,Nowak, J.,Wator-Wilk, E.,Grudnik, P.,Kowalczyk, D.,Koziel, J.,Mydel, P.,Poreba, M.,Kantyka, T.
Glycosaminoglycans activate peptidylarginine deiminase 4 by enhancing calcium affinity.
Proc.Natl.Acad.Sci.USA, 122:e2508369122-e2508369122, 2025

PubMed 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.

PubMed: 41166417
DOI: 10.1073/pnas.2508369122

Experimental method

ELECTRON MICROSCOPY (2.96 Å)