Myelin localization of peptidylarginine deiminases 2 and 4: comparison of PAD2 and PAD4 activities.
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.
Wood
Dorothy D
DD
Molecular Structure and Function, The Hospital for Sick Children, Toronto, ON, Canada.
Ackerley
Cameron A
CA
Brand
Ben van den
Bv
Zhang
Li
L
Raijmakers
Reinout
R
Mastronardi
Fabrizio G
FG
Moscarello
Mario A
MA
D000818:Animals; D001120:Arginine / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002956:Citrulline / Q000096:biosynthesis*; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D004676:Myelin Basic Protein / Q000378:metabolism*; D009186:Myelin Sheath / Q000201:enzymology*; D010713:Phosphatidylcholines / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D000080064:Protein-Arginine Deiminase Type 2; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases
D004676:Myelin Basic Protein; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D002956:Citrulline; D001120:Arginine; D006867:Hydrolases; C000620352:PADI2 protein, human; C000629235:PADI4 protein, human; D000080064:Protein-Arginine Deiminase Type 2; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; C552151:peptidylarginine deiminase 4, mouse