citrullination

Citrullination, also called deimination, is a post-translational modification in which arginine residues are enzymatically converted to citrulline by peptidylarginine deiminases (PADs). The reaction hydrolyzes the guanidinium group, releasing ammonia and neutralizing a positive charge on arginine. The modification does not cleave the peptide bond and can alter protein folding, interactions, and function. PAD enzymes are calcium-dependent and require elevated intracellular calcium for activity. In humans, the PAD family includes PAD1-PAD4 and PAD6, with PAD2 and PAD4 the most studied; other members are variably expressed. PADs target a wide range of substrates, including histones and cytoskeletal and enzyme proteins, leading to changes in localization and activity.

Physiological roles include regulation of gene expression by histone citrullination, chromatin remodeling, and participation in immune responses. In neutrophils, PAD4-driven histone citrullination promotes chromatin decondensation and the formation of neutrophil extracellular traps (NETs) in a process called NETosis, which contributes to pathogen defense but can also drive inflammation.

Pathological citrullination is linked to autoimmune and inflammatory diseases, most notably rheumatoid arthritis, where autoantibodies against citrullinated proteins (ACPAs) are common and serve as diagnostic markers. Citrullination is also studied in cancer and neurodegenerative diseases, though causal roles are less clear. Detection methods include mass spectrometry-based proteomics and antibodies specific for citrulline-containing epitopes. PAD activity can be modulated by calcium levels and can be inhibited with small-molecule inhibitors used in research and investigated for therapy.