3apn
Crystal structure of the human wild-type PAD4 protein
Structural highlights
DiseasePADI4_HUMAN Genetic variations in PADI4 are a cause of susceptibility to rheumatoid arthritis (RA) [MIM:180300. It is a systemic inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Note=Could have an important role in the pathogenesis of rheumatoid arthritis by increasing citrullination of proteins in rheumatoid arthritis synovial tissues, leading, in a cytokine-rich milieu, to a break in tolerance to citrullinated peptides processed and presented in the appropriate HLA context.[1] FunctionPADI4_HUMAN Catalyzes the citrullination/deimination of arginine residues of proteins. Citrullinates histone H3 at 'Arg-8' and/or 'Arg-17' and histone H4 at 'Arg-3', which prevents their methylation by CARM1 and HRMT1L2/PRMT1 and represses transcription. Citrullinates EP300/P300 at 'Arg-2142', which favors its interaction with NCOA2/GRIP1.[2] [3] Publication Abstract from PubMedPAD4 is a peptidylarginine deiminase that catalyzes citrullination, a type of post-translational modification. In this reaction, arginine residues in proteins are converted to citrulline. PAD4 promotes the deimination of arginine residues in histones and may regulate transcription in the context of the chromatin. Single-nucleotide polymorphisms (SNP) in the gene encoding PAD4 identified it as one of the genes associated with susceptibility to rheumatoid arthritis. The PAD4 SNP involve three amino-acid substitutions: Ser55 to Gly, Ala82 to Val and Ala112 to Gly. Autoantibodies for improperly citrullinated proteins have been found in rheumatoid arthritis patients, suggesting that the PAD4(SNP) mRNA is more stable than the conventional PAD4 mRNA and/or the PAD4(SNP) protein possesses a higher citrullination activity than the PAD4 protein. In order to study the effects of the three amino-acid substitutions found in PAD4(SNP), the crystal structure of PAD4(SNP) was determined and it was found that the amino-acid substitutions in PAD4(SNP) only induced conformational changes within the N-terminal domain, not in the active centre for citrullination located in the C-terminal domain. Biochemical analyses also suggested that the citrullination activity of PAD4(SNP) may not substantially differ from that of conventional PAD4. These structural and biochemical findings suggested that the improper protein citrullination found in rheumatoid arthritis patients is not caused by defects in the citrullination activity of PAD4(SNP) but by other reasons such as enhanced PAD4(SNP) mRNA stability. Structural and biochemical analyses of the human PAD4 variant encoded by a functional haplotype gene.,Horikoshi N, Tachiwana H, Saito K, Osakabe A, Sato M, Yamada M, Akashi S, Nishimura Y, Kagawa W, Kurumizaka H Acta Crystallogr D Biol Crystallogr. 2011 Feb;67(Pt 2):112-8. Epub 2011, Jan 8. PMID:21245532[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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