Myelin localization of peptidylarginine deiminases 2 and 4: comparison of PAD2 and PAD4 activities

• Published in: Laboratory investigation Vol. 88; no. 4; pp. 354 - 364
• Main Authors: Wood, Dorothy D, Ackerley, Cameron A, Brand, Ben van den, Zhang, Li, Raijmakers, Reinout, Mastronardi, Fabrizio G, Moscarello, Mario A
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-04-2008; Nature Publishing; Nature Publishing Group
• Subjects: Animals; Arginine - metabolism; Biological and medical sciences; Biotechnology; Blotting, Western; Brain - metabolism; Citrulline - biosynthesis; Fundamental and applied biological sciences. Psychology; Humans; Hydrolases - metabolism; Immunohistochemistry; Investigative techniques, diagnostic techniques (general aspects); Laboratory Medicine; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Myelin Basic Protein - metabolism; Myelin Sheath - enzymology; Pathology; Phosphatidylcholines - metabolism; Phosphatidylserines - metabolism; Protein-Arginine Deiminase Type 2; Protein-Arginine Deiminase Type 4; Protein-Arginine Deiminases; research-article; myelin; neurodegenerative disease; peptidylarginine deiminase; citrullinated myelin basic protein; multiple sclerosis; Biotechnology; Nervous system diseases; Multiple sclerosis; Myelin; Citrulline; Biological activity; Inflammatory disease; Basic protein; Central nervous system disease; Clinical biology; Localization; Comparative study
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.3700748

An understanding of the structure and composition of the myelin sheath is essential to understand the pathogenesis of demyelinating diseases such as multiple sclerosis (MS). The presence of citrulline in myelin proteins in particular myelin basic protein (MBP) causes an important change in myelin structure, which destabilizes myelin. The peptidylarginine deiminases (PADs) are responsible for converting arginine in proteins to citrulline. Two of these, PAD2 and PAD4, were localized to the myelin sheath by immunogold electron microscopy. Deimination of MBP by the recombinant forms of these enzymes showed that it was extensive, that is, PAD2 deiminated 18 of 19 arginyl residues in MBP, whereas PAD4 deiminated 14 of 19 residues. In the absence of PAD2 (the PAD2-knockout mouse) PAD4 remained active with limited deimination of arginyl residues. In myelin isolated from patients with MS, the amounts of both PAD2 and PAD4 enzymes were increased compared with that in normals, and the citrullinated proteins were also increased. These data support the view that an increase in citrullinated proteins resulting from increased PAD2 and 4 is an important change in the pathogenesis of MS.