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Review
. 2009 Sep;12(5):616-27.

Protein arginine deiminase 4 (PAD4): Current understanding and future therapeutic potential

Justin E Jones  1 , Corey P Causey, Bryan Knuckley, Jessica L Slack-Noyes, Paul R Thompson
Affiliations
Review

Protein arginine deiminase 4 (PAD4): Current understanding and future therapeutic potential

Justin E Jones et al. Curr Opin Drug Discov Devel. 2009 Sep.

Abstract

The protein arginine deiminases (PADs), and in particular PAD4, have emerged as potential therapeutic targets for the treatment of rheumatoid arthritis (RA). In this review, evidence linking dysregulated PAD activity to the onset and progression of RA is presented, and the potential role of such aberrant activity in other human diseases, such as multiple sclerosis and cancer, is discussed. The known physiological roles of the PADs, particularly PAD4, and current knowledge regarding PAD structure, catalysis and inhibition are also described.

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Figures

Figure 1
Figure 1
PADs catalyze the hydrolytic deimination of protein arginine to produce protein citrulline and ammonia.
Figure 2
Figure 2
Crystal structure of the PAD4•Ca2+ •Benzoyl Arginine Amide (BAA) complex. The C-terminal catalytic domain is shown in blue. The N-terminal domain contains two immunoglobulin-like subdomains (red and green, respectively). There are five Ca2+ binding sites (black). Insert shows the location of the RA-associated single nucleotide polymorphisms (SNPs), S55G, A82V, and A112G.
Figure 3
Figure 3
Active site of PAD4. A) Position of active site residues in the apoenzyme (dark grey) and calcium-bound form of the enzyme (light grey). B) Proposed catalytic mechanism. Adapted from [53].
Figure 3
Figure 3
Active site of PAD4. A) Position of active site residues in the apoenzyme (dark grey) and calcium-bound form of the enzyme (light grey). B) Proposed catalytic mechanism. Adapted from [53].
Figure 4
Figure 4
Diagram of PAD4 bound to a histone H3 tail mimic. Critical binding contacts are indicated by the dashed lines. Adapted from [54].
Figure 5
Figure 5
PAD4 inhibitors. aEnzyme was incubated at 52 °C for 30 min with 50 mM HEPES (pH 7.6), CaCl2(5 mM), DTT (2 mM), and BAEE (5 mM). bAfter preincubating the enzyme with inhibitor, 100 mM Tris-HCl (pH 7.6), CaCl2 (10 mM), DTT (2 mM), and NaCl (50 mM) at 37 °C for 15 min, BAEE (1 mM final) was added. cReactions were carried out in 100 mM Tris-HCl (pH 7.6), CaCl2 (10 mM), DTT (1 mM), and Bz-Arg (0.1 mM) at 37 °C for 40 or 60 min. dReactions were carried out in 100 mM Tris-HCl (pH 7.6), CaCl2 (10 mM), DTT (5 mM), and BAEE (5 mM) at 37 °C for 10 min. eReactions were carried out in 100 mM HEPES (pH 7.6), CaCl2 (10 mM), TCEP (0.5 mM), NaCl (50 mM), and BAEE (10 mM final) at 37 °C for 15 min.
See this image and copyright information in PMC

References

    1. Rogers GE, Simmonds DH. Content of citrulline and other amino-acids in a protein of hair follicles. Nature. 1958;182(4629):186–187. - PubMed

    1. Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest. 1998;101(1):273–281. This report described, for the first time, that RA associated autoantibodies recognize the citrullinated proteins.

    1. Vossenaar ER, Zendman AJ, van Venrooij WJ, Pruijn GJ. PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. Bioessays. 2003;25(11):1106–1118. An excellent review of the PAD family of enzymes.

    1. Cuthbert GL, Daujat S, Snowden AW, Erdjument-Bromage H, Hagiwara T, Yamada M, Schneider R, Gregory PD, Tempst P, Bannister AJ, Kouzarides T. Histone deimination antagonizes arginine methylation. Cell. 2004;118(5):545–553. This paper and ref. 5 provided the first evidence that PAD4 regulates gene transcription.

    1. Wang Y, Wysocka J, Sayegh J, Lee YH, Perlin JR, Leonelli L, Sonbuchner LS, McDonald CH, Cook RG, Dou Y, Roeder RG, et al. Human PAD4 Regulates Histone Arginine Methylation Levels via Demethylimination. Science. 2004;306:279–283. This paper and ref. 4 provided the first evidence that PAD4 regulates gene transcription.

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