Citrullinating

Citrullinating refers to the enzymatic modification of proteins in which arginine residues are converted to citrulline by the family of peptidylarginine deiminases (PADs). This post-translational modification is calcium-dependent and changes the chemical properties of the modified residue, often reducing positive charge and altering hydrogen-bonding patterns. As a result, citrullination can affect protein folding, interactions, localization, and antigenicity.

Enzymes and mechanism: The PAD family includes several isozymes (notably PAD2 and PAD4 in humans) that catalyze citrullination. The reaction requires elevated intracellular calcium and produces ammonia as a byproduct. Different PADs have tissue-specific patterns of expression and substrate preferences, leading to diverse effects in cells ranging from neutrophils to neurons.

Biological roles: Histone citrullination by PAD4 is implicated in chromatin decondensation and transcriptional regulation. In neutrophils, PAD4 drives citrullination of histones during the formation of neutrophil extracellular traps (NETs). Citrullination also modifies structural or cytoskeletal proteins such as vimentin and keratins, and is involved in skin barrier formation and myelin maintenance in some contexts.

Clinical significance: Abnormal citrullination is linked to autoimmune responses, particularly in rheumatoid arthritis, where antibodies against citrullinated proteins (ACPA) are common and diagnostically relevant. PAD activity is a potential therapeutic target, and selective PAD inhibitors are under investigation. Detection of citrullinated residues can be achieved by specific antibodies or mass spectrometry-based proteomics.