title: Comparison of enzymatic properties between hPADI2 and hPADI4.
abstract: In the sera of rheumatoid arthritis (RA) patients, autoantibodies directed to citrullinated proteins are found with high specificity for RA. Peptidylarginine deiminases (PADIs) are enzymes responsible for protein citrullination. Among many isoforms of PADIs, only PADI4 has been identified as an RA-susceptibility gene. To understand the mechanisms of the initiation and progression of RA, we compared the properties of two PADIs, human PADI2 and human PADI4, which are present in the synovial tissues of RA patients. We confirmed their precise distribution in the RA synovium and compared the stability, Ca2+ dependency, optimal pH range, and substrate specificity. Small but significant differences were found in the above-mentioned properties between hPADI2 and hPADI4. Using LC/MS/MS analysis, we identified the sequences in human fibrinogen indicating that hPADI2 and hPADI4 citrullinate in different manners. Our results indicate that hPADI2 and hPADI4 have different roles under physiological and pathological conditions. Further studies are needed for the better understanding of the role of hPADIs in the initiation and progression of RA.
authors.affiliation: Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Nakayama-Hamada
authors.forename: Akari
authors.initials: A
authors.lastname: Suzuki
authors.forename: Kazuishi
authors.initials: K
authors.lastname: Kubota
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takazawa
authors.forename: Mizuko
authors.initials: M
authors.lastname: Ohsaka
authors.forename: Reimi
authors.initials: R
authors.lastname: Kawaida
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ono
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kasuya
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Furukawa
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine / Q000737:chemistry / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000473:pathology; D002118:Calcium / Q000494:pharmacology; D002384:Catalysis; D002956:Citrulline / Q000737:chemistry / Q000378:metabolism; D005340:Fibrinogen / Q000737:chemistry / Q000378:metabolism; D000091344:Filaggrin Proteins; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006867:Hydrolases / Q000378:metabolism*; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008969:Molecular Sequence Data; D011489:Protein Denaturation; D000080064:Protein-Arginine Deiminase Type 2; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D013379:Substrate Specificity; D013583:Synovial Membrane / Q000201:enzymology / Q000473:pathology
chemical_list: C115499:BBeta fibrinogen; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; C464794:fibrinogen Aalpha; D002956:Citrulline; D005340:Fibrinogen; 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; D002118:Calcium