Citrullination

Citrullination is a post-translational modification of proteins where the amino acid arginine is converted into citrulline by the enzyme family known as peptidylarginine deiminases (PADs). This process involves the hydrolysis of arginine into citrulline, resulting in a change in the protein's structure and function. Citrullination plays a crucial role in various physiological and pathological processes, including cell death, gene expression, and the development of autoimmune diseases such as rheumatoid arthritis (RA).

Process

The citrullination process is catalyzed by the PAD enzymes, which are calcium-dependent. There are five known PAD isozymes in humans, PAD1, PAD2, PAD3, PAD4, and PAD6, each with distinct tissue distributions and substrate specificities. The conversion of arginine to citrulline involves the deimination of the guanidino group of arginine, resulting in the production of citrulline and ammonia. This modification can affect the protein's charge, conformation, and the ability to form hydrogen bonds, thereby altering its function and interactions with other molecules.

Biological Significance

Citrullination has been implicated in various biological processes. In the skin, it is involved in the formation of the epidermal barrier. In the brain, it can affect myelin basic protein function, which is significant in the context of multiple sclerosis. In the immune system, citrullination alters the structure of histones, affecting gene expression and promoting inflammation.

Pathological Significance

The pathological significance of citrullination is most notably observed in rheumatoid arthritis, where citrullinated proteins are targeted by autoantibodies known as anti-citrullinated protein antibodies (ACPAs). The presence of ACPAs is a hallmark of RA and is used in the diagnosis of the disease. Citrullination is also associated with other autoimmune diseases, including multiple sclerosis, Alzheimer's disease, and cancer, suggesting a broad impact on human health.

Detection and Clinical Relevance

The detection of citrullinated proteins and ACPAs is crucial for the diagnosis and management of diseases like RA. Various assays, including the anti-cyclic citrullinated peptide (anti-CCP) test, are used clinically to detect ACPAs. The presence of these antibodies often precedes the clinical onset of RA, making them valuable predictive markers.

Conclusion

Citrullination is a significant post-translational modification with wide-ranging effects on protein function and disease. Understanding the role of citrullination and PAD enzymes in health and disease can provide insights into the mechanisms of autoimmune diseases and lead to the development of novel therapeutic strategies.