Skip to main content
SpringerLink
Log in
Book cover

Protein Deimination in Human Health and Disease pp 377–427Cite as

Picking the PAD Lock: Chemical and Biological Approaches to Identify PAD Substrates and Inhibitors

  • Chapter
  • First Online:

Abstract

In this chapter, we first introduce the protein arginine deiminases (PADs) and then highlight several chemical and biological tools and methods that have greatly enhanced our understanding of the role of the human PADs in health and disease. While the detection of citrullinated proteins has classically proven difficult, new chemical probes that expand our detection capabilities past the realm of antibodies are proving pivotal in identifying new PAD substrates. The continued discovery of the role PADs play in multiple inflammatory diseases and cancer makes them viable therapeutic targets and drives the continued structure-based development of potent and specific inhibitors and chemical probes for this enzyme family.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   159.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Adessi C, Soto C (2002) Converting a peptide into a drug: strategies to improve stability and bioavailability. Curr Med Chem 9:963–978

    PubMed  CAS  Google Scholar 

  • Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J (1996) Human ICE/CED-3 protease nomenclature. Cell 87:171

    PubMed  CAS  Google Scholar 

  • Andrade F, Darrah E, Gucek M, Cole RN, Rosen A, Zhu X (2010) Autocitrullination of human peptidyl arginine deiminase type 4 regulates protein citrullination during cell activation. Arthritis Rheum 62:1630–1640

    PubMed  CAS  Google Scholar 

  • Arai T, Kusubata M, Kohsaka T, Shiraiwa M, Sugawara K, Takahara H (1995) Mouse uterus peptidylarginine deiminase is expressed in decidual cells during pregnancy. J Cell Biochem 58:269–278

    PubMed  CAS  Google Scholar 

  • Arita K, Hashimoto H, Shimizu T, Nakashima K, Yamada M, Sato M (2004) Structural basis for Ca2+-induced activation of human PAD4. Nat Struct Mol Biol 11:777–783

    PubMed  CAS  Google Scholar 

  • Arita K, Shimizu T, Hashimoto H, Hidaka Y, Yamada M, Sato M (2006) Structural basis for histone N-terminal recognition by human peptidylarginine deiminase 4. Proc Natl Acad Sci U S A 103:5291–5296

    PubMed  CAS  Google Scholar 

  • Asaga H, Yamada M, Senshu T (1998) Selective deimination of vimentin in calcium ionophore-induced apoptosis of mouse peritoneal macrophages. Biochem Biophys Res Commun 243:641–646

    PubMed  CAS  Google Scholar 

  • Baranczewski P, Stanczak A, Sundberg K, Svensson R, Wallin A, Jansson J, Garberg P, Postlind H (2006) Introduction to in vitro estimation of metabolic stability and drug interactions of new chemical entities in drug discovery and development. Pharmacol Rep 58:453–472

    PubMed  CAS  Google Scholar 

  • Barton A, Bowes J, Eyre S, Spreckley K, Hinks A, John S, Worthington J (2004) A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population. Arthritis Rheum 50:1117–1121

    PubMed  CAS  Google Scholar 

  • Beall HD, Mulcahy RT, Siegel D, Traver RD, Gibson NW, Ross D (1994) Metabolism of bioreductive antitumor compounds by purified rat and human DT-diaphorases. Cancer Res 54:3196–3201

    PubMed  CAS  Google Scholar 

  • Beall HD, Murphy AM, Siegel D, Hargreaves RH, Butler J, Ross D (1995) Nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase (DT-diaphorase) as a target for bioreductive antitumor quinones: quinone cytotoxicity and selectivity in human lung and breast cancer cell lines. Mol Pharmacol 48:499–504

    PubMed  CAS  Google Scholar 

  • Bertucci F, Borie N, Ginestier C, Groulet A, Charafe-Jauffret E, Adelaide J, Geneix J, Bachelart L, Finetti P, Koki A et al (2004) Identification and validation of an ERBB2 gene expression signature in breast cancers. Oncogene 23:2564–2575

    PubMed  CAS  Google Scholar 

  • Bicker KL, Anguish L, Chumanevich AA, Cameron MD, Cui X, Witalison E, Subramanian V, Zhang X, Chumanevich AP, Hofseth LJ et al (2012) D-Amino acid-based protein arginine deiminase inhibitors: synthesis, pharmacokinetics, and in cellulo efficacy. ACS Med Chem Lett 3:1081–1085

    PubMed  CAS  Google Scholar 

  • Blick T, Hugo H, Widodo E, Waltham M, Pinto C, Mani SA, Weinberg RA, Neve RM, Lenburg ME, Thompson EW (2010) Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44(hi/)CD24 (lo/-) stem cell phenotype in human breast cancer. J Mammary Gland Biol Neoplasia 15:235–252

    PubMed  Google Scholar 

  • Borregaard N (2010) Neutrophils, from marrow to microbes. Immunity 33:657–670

    PubMed  CAS  Google Scholar 

  • Bozdag M, Dreker T, Henry C, Tosco P, Vallaro M, Fruttero R, Scozzafava A, Carta F, Supuran CT (2013) Novel small molecule protein arginine deiminase 4 (PAD4) inhibitors. Bioorg Med Chem Lett 23:715–719

    Google Scholar 

  • Burr ML, Naseem H, Hinks A, Eyre S, Gibbons LJ, Bowes J, Wilson AG, Maxwell J, Morgan AW, Emery P et al (2010) PADI4 genotype is not associated with rheumatoid arthritis in a large UK Caucasian population. Ann Rheum Dis 69:666–670

    PubMed  CAS  Google Scholar 

  • Calabrese R, Zampieri M, Mechelli R, Annibali V, Guastafierro T, Ciccarone F, Coarelli G, Umeton R, Salvetti M, Caiafa P (2012) Methylation-dependent PAD2 upregulation in multiple sclerosis peripheral blood. Mult Scler 18:299–304

    PubMed  CAS  Google Scholar 

  • Causey CP, Jones JE, Slack JL, Kamei D, Jones LE, Subramanian V, Knuckley B, Ebrahimi P, Chumanevich AA, Luo Y et al (2011) The development of N-alpha-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-alpha-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine) as second generation protein arginine deiminase (PAD) inhibitors. J Med Chem 54:6919–6935

    PubMed  CAS  Google Scholar 

  • Chang X, Han J (2006) Expression of peptidylarginine deiminase type 4 (PAD4) in various tumors. Mol Carcinog 45:183–196

    PubMed  CAS  Google Scholar 

  • Chang X, Han J, Pang L, Zhao Y, Yang Y, Shen Z (2009) Increased PADI4 expression in blood and tissues of patients with malignant tumors. BMC Cancer 9:40

    PubMed  Google Scholar 

  • Chang X, Yamada R, Sawada T, Suzuki A, Kochi Y, Yamamoto K (2005) The inhibition of antithrombin by peptidylarginine deiminase 4 may contribute to pathogenesis of rheumatoid arthritis. Rheumatology (Oxford) 44:293–298

    CAS  Google Scholar 

  • Chen CC, Isomoto H, Narumi Y, Sato K, Oishi Y, Kobayashi T, Yanagihara K, Mizuta Y, Kohno S, Tsukamoto K (2008) Haplotypes of PADI4 susceptible to rheumatoid arthritis are also associated with ulcerative colitis in the Japanese population. Clin Immunol 126:165–171

    PubMed  CAS  Google Scholar 

  • Cherrington BD, Morency E, Struble AM, Coonrod SA, Wakshlag JJ (2010) Potential role for peptidylarginine deiminase 2 (PAD2) in citrullination of canine mammary epithelial cell histones. PLoS One 5:e11768

    PubMed  Google Scholar 

  • Cherrington BD, Zhang X, McElwee JL, Morency E, Anguish LJ, Coonrod SA (2012) Potential role for PAD2 in gene regulation in breast cancer cells. PLoS One 7:e41242

    PubMed  CAS  Google Scholar 

  • Chumanevich AA, Causey CP, Knuckley BA, Jones JE, Poudyal D, Chumanevich AP, Davis T, Matesic LE, Thompson PR, Hofseth LJ (2011) Suppression of colitis in mice by Cl-amidine: a novel peptidylarginine deiminase (Pad) inhibitor. Am J Physiol Gastrointest Liver Physiol 300:G929–G938

    PubMed  CAS  Google Scholar 

  • Cuthbert GL, Daujat S, Snowden AW, Erdjument-Bromage H, Hagiwara T, Yamada M, Schneider R, Gregory PD, Tempst P, Bannister AJ et al (2004) Histone deimination antagonizes arginine methylation. Cell 118:545–553

    PubMed  CAS  Google Scholar 

  • Darrah E, Rosen A, Giles JT, Andrade F (2012) Peptidylarginine deiminase 2, 3, and 4 have distinct specificities against cellular substrates: novel insights into autoantigen selection in rheumatoid arthritis. Ann Rheum Dis 71:92–98

    PubMed  CAS  Google Scholar 

  • Dawson PJ, Wolman SR, Tait L, Heppner GH, Miller FR (1996) MCF10AT: a model for the evolution of cancer from proliferative breast disease. Am J Pathol 148:313–319

    PubMed  CAS  Google Scholar 

  • De Rycke L, Nicholas AP, Cantaert T, Kruithof E, Echols JD, Vandekerckhove B, Veys EM, De Keyser F, Baeten D (2005) Synovial intracellular citrullinated proteins colocalizing with peptidyl arginine deiminase as pathophysiologically relevant antigenic determinants of rheumatoid arthritis-specific humoral autoimmunity. Arthritis Rheum 52:2323–2330

    PubMed  Google Scholar 

  • Drenth J, Kalk KH, Swen HM (1976) Binding of chloromethyl ketone substrate analogues to crystalline papain. Biochemistry 15:3731–3738

    PubMed  CAS  Google Scholar 

  • Feng D, Imasawa T, Nagano T, Kikkawa M, Takayanagi K, Ohsawa T, Akiyama K, Ishigami A, Toda T, Mitarai T et al (2005) Citrullination preferentially proceeds in glomerular Bowman’s capsule and increases in obstructive nephropathy. Kidney Int 68:84–95

    PubMed  CAS  Google Scholar 

  • Foulquier C, Sebbag M, Clavel C, Chapuy-Regaud S, Al Badine R, Mechin MC, Vincent C, Nachat R, Yamada M, Takahara H et al (2007) Peptidyl arginine deiminase type 2 (PAD-2) and PAD-4 but not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation. Arthritis Rheum 56:3541–3553

    PubMed  CAS  Google Scholar 

  • Fujisaki M, Sugawara K (1981) Properties of peptidylarginine deiminase from the epidermis of newborn rats. J Biochem 89:257–263

    PubMed  CAS  Google Scholar 

  • Galkin A, Lu X, Dunaway-Mariano D, Herzberg O (2005) Crystal structures representing the Michaelis complex and the thiouronium reaction intermediate of Pseudomonas aeruginosa arginine deiminase. J Biol Chem 280:34080–34087

    PubMed  CAS  Google Scholar 

  • Gandjbakhch F, Fajardy I, Ferre B, Dubucquoi S, Flipo RM, Roger N, Solau-Gervais E (2009) A functional haplotype of PADI4 gene in rheumatoid arthritis: positive correlation in a French population. J Rheumatol 36:881–886

    PubMed  CAS  Google Scholar 

  • Girbal-Neuhauser E, Durieux JJ, Arnaud M, Dalbon P, Sebbag M, Vincent C, Simon M, Senshu T, Masson-Bessiere C, Jolivet-Reynaud C et al (1999) The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues. J Immunol 162:585–594

    PubMed  CAS  Google Scholar 

  • Guo Q, Bedford MT, Fast W (2011) Discovery of peptidylarginine deiminase-4 substrates by protein array: antagonistic citrullination and methylation of human ribosomal protein S2. Mol Biosyst 7:2286–2295

    PubMed  CAS  Google Scholar 

  • Guo Q, Fast W (2011) Citrullination of inhibitor of growth 4 (ING4) by peptidylarginine deminase 4 (PAD4) disrupts the interaction between ING4 and p53. J Biol Chem 286:17069–17078

    PubMed  CAS  Google Scholar 

  • Hagiwara T, Hidaka Y, Yamada M (2005) Deimination of histone H2A and H4 at arginine 3 in HL-60 granulocytes. Biochemistry 44:5827–5834

    PubMed  CAS  Google Scholar 

  • Hagiwara T, Nakashima K, Hirano H, Senshu T, Yamada M (2002) Deimination of arginine residues in nucleophosmin/B23 and histones in HL-60 granulocytes. Biochem Biophys Res Commun 290:979–983

    PubMed  CAS  Google Scholar 

  • Heppner GH, Wolman SR (1999) MCF-10AT: a model for human breast cancer development. Breast J 5:122–129

    PubMed  Google Scholar 

  • Hidaka Y, Hagiwara T, Yamada M (2005) Methylation of the guanidino group of arginine residues prevents citrullination by peptidylarginine deiminase IV. FEBS Lett 579:4088–4092

    PubMed  CAS  Google Scholar 

  • Hojo-Nakashima I, Sato R, Nakashima K, Hagiwara T, Yamada M (2009) Dynamic expression of peptidylarginine deiminase 2 in human monocytic leukaemia THP-1 cells during macrophage differentiation. J Biochem 146:471–479

    PubMed  CAS  Google Scholar 

  • Holm A, Rise F, Sessler N, Sollid LM, Undheim K, Fleckenstein B (2006) Specific modification of peptide-bound citrulline residues. Anal Biochem 352:68–76

    PubMed  CAS  Google Scholar 

  • Ishida-Yamamoto A, Senshu T, Eady RA, Takahashi H, Shimizu H, Akiyama M, Iizuka H (2002) Sequential reorganization of cornified cell keratin filaments involving filaggrin-mediated compaction and keratin 1 deimination. J Invest Dermatol 118:282–287

    PubMed  CAS  Google Scholar 

  • Ishigami A, Ohsawa T, Hiratsuka M, Taguchi H, Kobayashi S, Saito Y, Murayama S, Asaga H, Toda T, Kimura N et al (2005) Abnormal accumulation of citrullinated proteins catalyzed by peptidylarginine deiminase in hippocampal extracts from patients with Alzheimer’s disease. J Neurosci Res 80:120–128

    PubMed  CAS  Google Scholar 

  • Jang B, Jeon YC, Choi JK, Park M, Kim JI, Ishigami A, Maruyama N, Carp RI, Kim YS, Choi EK (2012) Peptidylarginine deiminase modulates the physiological roles of enolase via citrullination: links between altered multifunction of enolase and neurodegenerative diseases. Biochem J 445:183–192

    PubMed  CAS  Google Scholar 

  • Jones JE, Causey CP, Knuckley B, Slack-Noyes JL, Thompson PR (2009) Protein arginine deiminase 4 (PAD4): current understanding and future therapeutic potential. Curr Opin Drug Discov Devel 12:616–627

    PubMed  CAS  Google Scholar 

  • Jones JE, Dreyton CJ, Flick H, Causey CP, Thompson PR (2010) Mechanistic studies of agmatine deiminase from multiple bacterial species. Biochemistry 49:9413–9423

    PubMed  CAS  Google Scholar 

  • Jones JE, Slack JL, Fang P, Zhang X, Subramanian V, Causey CP, Coonrod SA, Guo M, Thompson PR (2012) Synthesis and screening of a haloacetamidine containing library to identify PAD4 selective inhibitors. ACS Chem Biol 7:160–165

    PubMed  CAS  Google Scholar 

  • Kamata Y, Taniguchi A, Yamamoto M, Nomura J, Ishihara K, Takahara H, Hibino T, Takeda A (2009) Neutral cysteine protease bleomycin hydrolase is essential for the breakdown of deiminated filaggrin into amino acids. J Biol Chem 284:12829–12836

    PubMed  CAS  Google Scholar 

  • Kan R, Yurttas P, Kim B, Jin M, Wo L, Lee B, Gosden R, Coonrod SA (2011) Regulation of mouse oocyte microtubule and organelle dynamics by PADI6 and the cytoplasmic lattices. Dev Biol 350:311–322

    PubMed  CAS  Google Scholar 

  • Kanno T, Kawada A, Yamanouchi J, Yosida-Noro C, Yoshiki A, Shiraiwa M, Kusakabe M, Manabe M, Tezuka T, Takahara H (2000) Human peptidylarginine deiminase type III: molecular cloning and nucleotide sequence of the cDNA, properties of the recombinant enzyme, and immunohistochemical localization in human skin. J Invest Dermatol 115:813–823

    PubMed  CAS  Google Scholar 

  • Kearney PL, Bhatia M, Jones NG, Luo Y, Glascock MC, Catchings KL, Yamada M, Thompson PR (2005) Kinetic characterization of protein arginine deiminase 4: a transcriptional corepressor implicated in the onset and progression of rheumatoid arthritis. Biochemistry 44:10570–10582

    PubMed  CAS  Google Scholar 

  • Kessenbrock K, Krumbholz M, Schonermarck U, Back W, Gross WL, Werb Z, Grone HJ, Brinkmann V, Jenne DE (2009) Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med 15:623–625

    PubMed  CAS  Google Scholar 

  • Kim B, Kan R, Anguish L, Nelson LM, Coonrod SA (2010) Potential role for MATER in cytoplasmic lattice formation in murine oocytes. PLoS One 5:e12587

    PubMed  Google Scholar 

  • Kizawa K, Takahara H, Troxler H, Kleinert P, Mochida U, Heizmann CW (2008) Specific citrullination causes assembly of a globular S100A3 homotetramer: a putative Ca2+ modulator matures human hair cuticle. J Biol Chem 283:5004–5013

    PubMed  CAS  Google Scholar 

  • Knipp M, Vasak M (2000) A colorimetric 96-well microtiter plate assay for the determination of enzymatically formed citrulline. Anal Biochem 286:257–264

    PubMed  CAS  Google Scholar 

  • Knuckley B, Bhatia M, Thompson PR (2007) Protein arginine deiminase 4: evidence for a reverse protonation mechanism. Biochemistry 46:6578–6587

    PubMed  CAS  Google Scholar 

  • Knuckley B, Causey CP, Jones JE, Bhatia M, Dreyton CJ, Osborne TC, Takahara H, Thompson PR (2010a) Substrate specificity and kinetic studies of PADs 1, 3, and 4 identify potent and selective inhibitors of protein arginine deiminase 3. Biochemistry 49:4852–4863

    PubMed  CAS  Google Scholar 

  • Knuckley B, Causey CP, Pellechia PJ, Cook PF, Thompson PR (2010b) Haloacetamidine-based inactivators of protein arginine deiminase 4 (PAD4): evidence that general acid catalysis promotes efficient inactivation. Chembiochem 11:161–165

    PubMed  CAS  Google Scholar 

  • Knuckley B, Jones JE, Bachovchin DA, Slack J, Causey CP, Brown SJ, Rosen H, Cravatt BF, Thompson PR (2010c) A fluopol-ABPP HTS assay to identify PAD inhibitors. Chem Commun (Camb) 46:7175–7177

    CAS  Google Scholar 

  • Knuckley B, Luo Y, Thompson PR (2008) Profiling protein arginine deiminase 4 (PAD4): a novel screen to identify PAD4 inhibitors. Bioorg Med Chem 16:739–745

    PubMed  CAS  Google Scholar 

  • Kreutter K, Steinmetz AC, Liang TC, Prorok M, Abeles RH, Ringe D (1994) Three-dimensional structure of chymotrypsin inactivated with (2S)-N-acetyl-L-alanyl-L-phenylalanyl alpha-chloroethane: implications for the mechanism of inactivation of serine proteases by chloroketones. Biochemistry 33:13792–13800

    PubMed  CAS  Google Scholar 

  • Kubilus J, Baden HP (1983) Purification and properties of a brain enzyme which deiminates proteins. Biochim Biophys Acta 745:285–291

    PubMed  CAS  Google Scholar 

  • Lee HJ, Joo M, Abdolrasulnia R, Young DG, Choi I, Ware LB, Blackwell TS, Christman BW (2010) Peptidylarginine deiminase 2 suppresses inhibitory {kappa}B kinase activity in lipopolysaccharide-stimulated RAW 264.7 macrophages. J Biol Chem 285:39655–39662

    PubMed  CAS  Google Scholar 

  • Lee YH, Coonrod SA, Kraus WL, Jelinek MA, Stallcup MR (2005) Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination. Proc Natl Acad Sci U S A 102:3611–3616

    PubMed  CAS  Google Scholar 

  • Lee YH, Rho YH, Choi SJ, Ji JD, Song GG (2007) PADI4 polymorphisms and rheumatoid arthritis susceptibility: a meta-analysis. Rheumatol Int 27:827–833

    PubMed  CAS  Google Scholar 

  • Leshner M, Wang S, Lewis C, Zheng H, Chen XA, Santy L, Wang Y (2012) PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures. Front Immunol 3:307

    PubMed  Google Scholar 

  • Li P, Li M, Lindberg MR, Kennett MJ, Xiong N, Wang Y (2010) PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med 207:1853–1862

    PubMed  CAS  Google Scholar 

  • Li P, Yao H, Zhang Z, Li M, Luo Y, Thompson PR, Gilmour DS, Wang Y (2008) Regulation of p53 target gene expression by peptidylarginine deiminase 4. Mol Cell Biol 28:4745–4758

    PubMed  CAS  Google Scholar 

  • Liao YF, Hsieh HC, Liu GY, Hung HC (2005) A continuous spectrophotometric assay method for peptidylarginine deiminase type 4 activity. Anal Biochem 347:176–181

    PubMed  CAS  Google Scholar 

  • Linsky T, Fast W (2010) Mechanistic similarity and diversity among the guanidine-modifying members of the pentein superfamily. Biochim Biophys Acta 1804:1943–1953

    PubMed  CAS  Google Scholar 

  • Liu YL, Chiang YH, Liu GY, Hung HC (2011) Functional role of dimerization of human peptidylarginine deiminase 4 (PAD4). PLoS One 6:e21314

    PubMed  CAS  Google Scholar 

  • Logters T, Margraf S, Altrichter J, Cinatl J, Mitzner S, Windolf J, Scholz M (2009) The clinical value of neutrophil extracellular traps. Med Microbiol Immunol 198:211–219

    PubMed  Google Scholar 

  • Loos T, Mortier A, Gouwy M, Ronsse I, Put W, Lenaerts JP, Van Damme J, Proost P (2008) Citrullination of CXCL10 and CXCL11 by peptidylarginine deiminase: a naturally occurring posttranslational modification of chemokines and new dimension of immunoregulation. Blood 112:2648–2656

    PubMed  CAS  Google Scholar 

  • Loos T, Opdenakker G, Van Damme J, Proost P (2009) Citrullination of CXCL8 increases this chemokine's ability to mobilize neutrophils into the blood circulation. Haematologica 94:1346–1353

    PubMed  CAS  Google Scholar 

  • Lundberg K, Nijenhuis S, Vossenaar ER, Palmblad K, van Venrooij WJ, Klareskog L, Zendman AJ, Harris HE (2005) Citrullinated proteins have increased immunogenicity and arthritogenicity and their presence in arthritic joints correlates with disease severity. Arthritis Res Ther 7:R458–R467

    PubMed  CAS  Google Scholar 

  • Luo Y, Arita K, Bhatia M, Knuckley B, Lee YH, Stallcup MR, Sato M, Thompson PR (2006a) Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization. Biochemistry 45:11727–11736

    PubMed  CAS  Google Scholar 

  • Luo Y, Knuckley B, Bhatia M, Thompson PR (2006b) Activity based protein profiling reagents for protein arginine deiminase 4 (PAD4): synthesis and in vitro evaluation of a fluorescently-labeled probe. J Am Chem Soc 128:14468–14469

    PubMed  CAS  Google Scholar 

  • Luo Y, Knuckley B, Lee YH, Stallcup MR, Thompson PR (2006c) A fluoro-acetamidine based inactivator of protein arginine deiminase 4 (PAD4): design, synthesis, and in vitro and in vivo evaluation. J Am Chem Soc 128:1092–1093

    PubMed  CAS  Google Scholar 

  • Mackay A, Tamber N, Fenwick K, Iravani M, Grigoriadis A, Dexter T, Lord CJ, Reis-Filho JS, Ashworth A (2009) A high-resolution integrated analysis of genetic and expression profiles of breast cancer cell lines. Breast Cancer Res Treat 118:481–498

    PubMed  CAS  Google Scholar 

  • Marcos V, Zhou Z, Yildirim AO, Bohla A, Hector A, Vitkov L, Wiedenbauer EM, Krautgartner WD, Stoiber W, Belohradsky BH et al (2010) CXCR2 mediates NADPH oxidase-independent neutrophil extracellular trap formation in cystic fibrosis airway inflammation. Nat Med 16:1018–1023

    PubMed  CAS  Google Scholar 

  • Mastronardi FG, Noor A, Wood DD, Paton T, Moscarello MA (2007) Peptidyl argininedeiminase 2 CpG island in multiple sclerosis white matter is hypomethylated. J Neurosci Res 85:2006–2016

    PubMed  CAS  Google Scholar 

  • Mastronardi FG, Wood DD, Mei J, Raijmakers R, Tseveleki V, Dosch HM, Probert L, Casaccia-Bonnefil P, Moscarello MA (2006) Increased citrullination of histone H3 in multiple sclerosis brain and animal models of demyelination: a role for tumor necrosis factor-induced peptidylarginine deiminase 4 translocation. J Neurosci 26:11387–11396

    PubMed  CAS  Google Scholar 

  • McElwee JL, Mohanan S, Griffith OL, Breuer HC, Anguish LJ, Cherrington BD, Palmer AM, Howe LR, Subramanian V, Causey CP et al (2012) Identification of PADI2 as a potential breast cancer biomarker and therapeutic target. BMC Cancer 12:500

    PubMed  CAS  Google Scholar 

  • Miller FR, Santner SJ, Tait L, Dawson PJ (2000) MCF10DCIS.com xenograft model of human comedo ductal carcinoma in situ. J Natl Cancer Inst 92:1185–1186

    PubMed  CAS  Google Scholar 

  • Miller SM, Simon RJ, Ng S, Zuckermann RN, Kerr JM, Moos WH (1995) Comparison of the proteolytic susceptibilities of homologous L-amino acid, D-amino acid, and N-substituted glycine peptide and peptoid oligomers. Drug Dev Res 35:20–32

    CAS  Google Scholar 

  • Moelants EA, Mortier A, Grauwen K, Ronsse I, Van Damme J, Proost P (2013) Citrullination of TNF-alpha by peptidylarginine deiminases reduces its capacity to stimulate the production of inflammatory chemokines. Cytokine 61:161–167

    PubMed  CAS  Google Scholar 

  • Moelants EA, Van Damme J, Proost P (2011) Detection and quantification of citrullinated chemokines. PLoS One 6:e28976

    PubMed  CAS  Google Scholar 

  • Mortier A, Loos T, Gouwy M, Ronsse I, Van Damme J, Proost P (2010) Posttranslational modification of the NH2-terminal region of CXCL5 by proteases or peptidylarginine Deiminases (PAD) differently affects its biological activity. J Biol Chem 285:29750–29759

    PubMed  CAS  Google Scholar 

  • Moscarello MA, Mak B, Nguyen TA, Wood DD, Mastronardi F, Ludwin SK (2002) Paclitaxel (Taxol) attenuates clinical disease in a spontaneously demyelinating transgenic mouse and induces remyelination. Mult Scler 8:130–138

    PubMed  CAS  Google Scholar 

  • Musse AA, Li Z, Ackerley CA, Bienzle D, Lei H, Poma R, Harauz G, Moscarello MA, Mastronardi FG (2008) Peptidylarginine deiminase 2 (PAD2) overexpression in transgenic mice leads to myelin loss in the central nervous system. Dis Model Mech 1:229–240

    PubMed  CAS  Google Scholar 

  • Nachat R, Mechin MC, Charveron M, Serre G, Constans J, Simon M (2005a) Peptidylarginine deiminase isoforms are differentially expressed in the anagen hair follicles and other human skin appendages. J Invest Dermatol 125:34–41

    PubMed  CAS  Google Scholar 

  • Nachat R, Mechin MC, Takahara H, Chavanas S, Charveron M, Serre G, Simon M (2005b) Peptidylarginine deiminase isoforms 1–3 are expressed in the epidermis and involved in the deimination of K1 and filaggrin. J Invest Dermatol 124:384–393

    PubMed  CAS  Google Scholar 

  • Nakashima K, Hagiwara T, Ishigami A, Nagata S, Asaga H, Kuramoto M, Senshu T, Yamada M (1999) Molecular characterization of peptidylarginine deiminase in HL-60 cells induced by retinoic acid and 1alpha, 25-dihydroxyvitamin D(3). J Biol Chem 274:27786–27792

    PubMed  CAS  Google Scholar 

  • Nakashima K, Hagiwara T, Yamada M (2002) Nuclear localization of peptidylarginine deiminase V and histone deimination in granulocytes. J Biol Chem 277:49562–49568

    PubMed  CAS  Google Scholar 

  • Nomura K (1992) Specificity and mode of action of the muscle-type protein-arginine deiminase. Arch Biochem Biophys 293:362–369

    PubMed  CAS  Google Scholar 

  • Obianyo O, Causey CP, Jones JE, Thompson PR (2011) Activity-based protein profiling of protein arginine methyltransferase 1. ACS Chem Biol 6:1127–1135

    PubMed  CAS  Google Scholar 

  • Oleson JJ, Calderella LA, Mjos KJ, Reith AR, Thie RS, Toplin I (1961) The effects of streptonigrin on experimental tumors. Antibiot Chemother 11:158–164

    CAS  Google Scholar 

  • Ordonez A, Martinez-Martinez I, Corrales FJ, Miqueo C, Minano A, Vicente V, Corral J (2009) Effect of citrullination on the function and conformation of antithrombin. FEBS J 276:6763–6772

    PubMed  CAS  Google Scholar 

  • Papayannopoulos V, Zychlinsky A (2009) NETs: a new strategy for using old weapons. Trends Immunol 30:513–521

    PubMed  CAS  Google Scholar 

  • Parseghian MH, Luhrs KA (2006) Beyond the walls of the nucleus: the role of histones in cellular signaling and innate immunity. Biochem Cell Biol 84:589–604

    PubMed  CAS  Google Scholar 

  • Powers JC, Asgian JL, Ekici OD, James KE (2002) Irreversible inhibitors of serine, cysteine, and threonine proteases. Chem Rev 102:4639–4750

    PubMed  CAS  Google Scholar 

  • Pritzker LB, Joshi S, Gowan JJ, Harauz G, Moscarello MA (2000) Deimination of myelin basic protein. 1. Effect of deimination of arginyl residues of myelin basic protein on its structure and susceptibility to digestion by cathepsin D. Biochemistry 39:5374–5381

    PubMed  CAS  Google Scholar 

  • Pritzker LB, Moscarello MA (1998) A novel microtubule independent effect of paclitaxel: the inhibition of peptidylarginine deiminase from bovine brain. Biochim Biophys Acta 1388:154–160

    PubMed  CAS  Google Scholar 

  • Proost P, Loos T, Mortier A, Schutyser E, Gouwy M, Noppen S, Dillen C, Ronsse I, Conings R, Struyf S et al (2008) Citrullination of CXCL8 by peptidylarginine deiminase alters receptor usage, prevents proteolysis, and dampens tissue inflammation. J Exp Med 205:2085–2097

    PubMed  CAS  Google Scholar 

  • Raijmakers R, Zendman AJ, Egberts WV, Vossenaar ER, Raats J, Soede-Huijbregts C, Rutjes FP, van Veelen PA, Drijfhout JW, Pruijn GJ (2007) Methylation of arginine residues interferes with citrullination by peptidylarginine deiminases in vitro. J Mol Biol 367:1118–1129

    PubMed  CAS  Google Scholar 

  • Raptopoulou A, Sidiropoulos P, Katsouraki M, Boumpas DT (2007) Anti-citrulline antibodies in the diagnosis and prognosis of rheumatoid arthritis: evolving concepts. Crit Rev Clin Lab Sci 44:339–363

    PubMed  CAS  Google Scholar 

  • Reilly HC, Sugiura K (1961) An antitumor spectrum of streptonigrin. Antibiot Chemother 11:174–177

    CAS  Google Scholar 

  • Rogers GE, Harding HW, Llewellyn-Smith IJ (1977) The origin of citrulline-containing proteins in the hair follicle and the chemical nature of trichohyalin, an intracellular precursor. Biochim Biophys Acta 495:159–175

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Rogers GE, Taylor LD (1977) The enzymic derivation of citrulline residues from arginine residues in situ during the biosynthesis of hair proteins that are cross-linked by isopeptide bonds. Adv Exp Med Biol 86A:283–294

    PubMed  CAS  Google Scholar 

  • Rohrbach AS, Slade DJ, Thompson PR, Mowen KA (2012) Activation of PAD4 in NET formation. Front Immunol 3:360

    PubMed  Google Scholar 

  • Rust HL, Thompson PR (2011) Kinase consensus sequences: a breeding ground for crosstalk. ACS Chem Biol 6:881–892

    PubMed  CAS  Google Scholar 

  • Savchenko AS, Inoue A, Ohashi R, Jiang S, Hasegawa G, Tanaka T, Hamakubo T, Kodama T, Aoyagi Y, Ushiki T et al (2011) Long pentraxin 3 (PTX3) expression and release by neutrophils in vitro and in ulcerative colitis. Pathol Int 61:290–297

    PubMed  CAS  Google Scholar 

  • Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ (1998) Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest 101:273–281

    PubMed  CAS  Google Scholar 

  • Schellekens GA, Visser H, de Jong BA, van den Hoogen FH, Hazes JM, Breedveld FC, van Venrooij WJ (2000) The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 43:155–163

    PubMed  CAS  Google Scholar 

  • Senshu T, Akiyama K, Ishigami A, Nomura K (1999a) Studies on specificity of peptidylarginine deiminase reactions using an immunochemical probe that recognizes an enzymatically deiminated partial sequence of mouse keratin K1. J Dermatol Sci 21:113–126

    PubMed  CAS  Google Scholar 

  • Senshu T, Akiyama K, Kan S, Asaga H, Ishigami A, Manabe M (1995) Detection of deiminated proteins in rat skin: probing with a monospecific antibody after modification of citrulline residues. J Invest Dermatol 105:163–169

    PubMed  CAS  Google Scholar 

  • Senshu T, Akiyama K, Nomura K (1999b) Identification of citrulline residues in the V subdomains of keratin K1 derived from the cornified layer of newborn mouse epidermis. Exp Dermatol 8:392–401

    PubMed  CAS  Google Scholar 

  • Senshu T, Kan S, Ogawa H, Manabe M, Asaga H (1996) Preferential deimination of keratin K1 and filaggrin during the terminal differentiation of human epidermis. Biochem Biophys Res Commun 225:712–719

    PubMed  CAS  Google Scholar 

  • Sharma P, Azebi S, England P, Christensen T, Moller-Larsen A, Petersen T, Batsche E, Muchardt C (2012) Citrullination of histone H3 interferes with HP1-mediated transcriptional repression. PLoS Genet 8:e1002934

    PubMed  CAS  Google Scholar 

  • Shirai H, Blundell TL, Mizuguchi K (2001) A novel superfamily of enzymes that catalyze the modification of guanidino groups. Trends Biochem Sci 26:465–468

    PubMed  CAS  Google Scholar 

  • Slack JL, Causey CP, Luo Y, Thompson PR (2011a) The development and use of clickable activity based protein profiling agents for protein arginine deiminase 4. ACS Chem Biol 6:466–476

    PubMed  CAS  Google Scholar 

  • Slack JL, Causey CP, Thompson PR (2011b) Protein arginine deiminase 4: a target for an epigenetic cancer therapy. Cell Mol Life Sci 68:709–720

    PubMed  CAS  Google Scholar 

  • Slack JL, Jones LE Jr, Bhatia MM, Thompson PR (2011c) Autodeimination of protein arginine deiminase 4 alters protein–protein interactions but not activity. Biochemistry 50:3997–4010

    PubMed  CAS  Google Scholar 

  • Snow AJ, Puri P, Acker-Palmer A, Bouwmeester T, Vijayaraghavan S, Kline D (2008) Phosphorylation-dependent interaction of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein (YWHA) with PADI6 following oocyte maturation in mice. Biol Reprod 79:337–347

    PubMed  CAS  Google Scholar 

  • Stensland ME, Pollmann S, Molberg O, Sollid LM, Fleckenstein B (2009) Primary sequence, together with other factors, influence peptide deimination by peptidylarginine deiminase-4. Biol Chem 390:99–107

    PubMed  CAS  Google Scholar 

  • Stone EM, Person MD, Costello NJ, Fast W (2005a) Characterization of a transient covalent adduct formed during dimethylarginine dimethylaminohydrolase catalysis. Biochemistry 44:7069–7078

    PubMed  CAS  Google Scholar 

  • Stone EM, Schaller TH, Bianchi H, Person MD, Fast W (2005b) Inactivation of two diverse enzymes in the amidinotransferase superfamily by 2-chloroacetamidine: dimethylargininase and peptidylarginine deiminase. Biochemistry 44:13744–13752

    PubMed  CAS  Google Scholar 

  • Struyf S, Noppen S, Loos T, Mortier A, Gouwy M, Verbeke H, Huskens D, Luangsay S, Parmentier M, Geboes K et al (2009) Citrullination of CXCL12 differentially reduces CXCR4 and CXCR7 binding with loss of inflammatory and anti-HIV-1 activity via CXCR4. J Immunol 182:666–674

    PubMed  CAS  Google Scholar 

  • Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama-Hamada M, Kawaida R, Ono M et al (2003) Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34:395–402

    PubMed  CAS  Google Scholar 

  • Tanikawa C, Espinosa M, Suzuki A, Masuda K, Yamamoto K, Tsuchiya E, Ueda K, Daigo Y, Nakamura Y, Matsuda K (2012) Regulation of histone modification and chromatin structure by the p53-PADI4 pathway. Nat Commun 3:676

    PubMed  Google Scholar 

  • Tanikawa C, Ueda K, Nakagawa H, Yoshida N, Nakamura Y, Matsuda K (2009) Regulation of protein citrullination through p53/PADI4 network in DNA damage response. Cancer Res 69:8761–8769

    PubMed  CAS  Google Scholar 

  • Tarcsa E, Marekov LN, Mei G, Melino G, Lee SC, Steinert PM (1996) Protein unfolding by peptidylarginine deiminase. Substrate specificity and structural relationships of the natural substrates trichohyalin and filaggrin. J Biol Chem 271:30709–30716

    PubMed  CAS  Google Scholar 

  • Teller MN, Wagshul SF, Woolley GW (1961) Transplantable human tumors in experimental chemotherapy: effects of streptonigrin on HS No. 1 and HEp No. 3 in the rat. Antibiot Chemother 11:165–173

    CAS  Google Scholar 

  • Terakawa H, Takahara H, Sugawara K (1991) Three types of mouse peptidylarginine deiminase: characterization and tissue distribution. J Biochem 110:661–666

    PubMed  CAS  Google Scholar 

  • Thompson PR, Fast W (2006) Histone citrullination by protein arginine deiminase: is arginine methylation a green light or a roadblock? ACS Chem Biol 1:433–441

    PubMed  CAS  Google Scholar 

  • Tocilj A, Schrag JD, Li Y, Schneider BL, Reitzer L, Matte A, Cygler M (2005) Crystal structure of N-succinylarginine dihydrolase AstB, bound to substrate and product, an enzyme from the arginine catabolic pathway of Escherichia coli. J Biol Chem 280:15800–15808

    PubMed  CAS  Google Scholar 

  • Trouw LA, Mahler M (2012) Closing the serological gap: promising novel biomarkers for the early diagnosis of rheumatoid arthritis. Autoimmun Rev 12:318–322

    PubMed  CAS  Google Scholar 

  • Tsuchida M, Minami N, Tsujimoto H, Fukazawa C, Takahara H, Sugawara K (1991) Molecular cloning of mouse peptidylarginine deiminase, and its possible isozyme cDNAs. Agric Biol Chem 55:295–297

    PubMed  CAS  Google Scholar 

  • Tugyi R, Uray K, Iván D, Fellinger E, Perkins A, Hudecz F (2005) Partial d-amino acid substitution: improved enzymatic stability and preserved Ab recognition of a MUC2 epitope peptide. Proc Natl Acad Sci U S A 102:413–418

    PubMed  CAS  Google Scholar 

  • Tutturen AE, Holm A, Jorgensen M, Stadtmuller P, Rise F, Fleckenstein B (2010) A technique for the specific enrichment of citrulline-containing peptides. Anal Biochem 403:43–51

    PubMed  CAS  Google Scholar 

  • Unno M, Kizawa K, Ishihara M, Takahara H (2012) Crystallization and preliminary X-ray crystallographic analysis of human peptidylarginine deiminase type III. Acta Crystallogr Sect F Struct Biol Cryst Commun 68:668–670

    PubMed  CAS  Google Scholar 

  • van Beers JJ, Raijmakers R, Alexander LE, Stammen-Vogelzangs J, Lokate AM, Heck AJ, Schasfoort RB, Pruijn GJ (2010) Mapping of citrullinated fibrinogen B-cell epitopes in rheumatoid arthritis by imaging surface plasmon resonance. Arthritis Res Ther 12:R219

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Wang Y, Li M, Stadler S, Correll S, Li P, Wang D, Hayama R, Leonelli L, Han H, Grigoryev SA et al (2009) Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J Cell Biol 184:205–213

    PubMed  CAS  Google Scholar 

  • Wang Y, Li P, Wang S, Hu J, Chen XA, Wu J, Fisher M, Oshaben K, Zhao N, Gu Y et al (2012) Anticancer PAD inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activity. J Biol Chem 287:25941–25953

    PubMed  CAS  Google Scholar 

  • Wang Y, Wysocka J, Sayegh J, Lee YH, Perlin JR, Leonelli L, Sonbuchner LS, McDonald CH, Cook RG, Dou Y et al (2004) Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306:279–283

    PubMed  CAS  Google Scholar 

  • Watanabe K, Senshu T (1989) Isolation and characterization of cDNA clones encoding rat skeletal muscle peptidylarginine deiminase. J Biol Chem 264:15255–15260

    PubMed  CAS  Google Scholar 

  • Weerapana E, Speers AE, Cravatt BF (2007) Tandem orthogonal proteolysis-activity-based protein profiling (TOP-ABPP)—a general method for mapping sites of probe modification in proteomes. Nat Protoc 2:1414–1425

    PubMed  CAS  Google Scholar 

  • Werle M, Bernkop-Schnürch A (2006) Strategies to improve plasma half life time of peptide and protein drugs. Amino Acids 30:351–367

    PubMed  CAS  Google Scholar 

  • Willis VC, Gizinski AM, Banda NK, Causey CP, Knuckley B, Cordova KN, Luo Y, Levitt B, Glogowska M, Chandra P et al (2011) N-α-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide, a protein arginine deiminase inhibitor, reduces the severity of murine collagen-induced arthritis. J Immunol 186:4396–4404

    PubMed  CAS  Google Scholar 

  • Wood DD, Ackerley CA, Brand B, Zhang L, Raijmakers R, Mastronardi FG, Moscarello MA (2008) Myelin localization of peptidylarginine deiminases 2 and 4: comparison of PAD2 and PAD4 activities. Lab Invest 88:354–364

    PubMed  CAS  Google Scholar 

  • Yamakoshi A, Ono H, Nishijyo T, Shiraiwa M, Takahara H (1998) Cloning of cDNA encoding a novel isoform (type IV) of peptidylarginine deiminase from rat epidermis. Biochim Biophys Acta 1386:227–232

    PubMed  CAS  Google Scholar 

  • Yao H, Li P, Venters BJ, Zheng S, Thompson PR, Pugh BF, Wang Y (2008) Histone arg modifications and p53 regulate the expression of OKL38, a mediator of apoptosis. J Biol Chem 283:20060–20068

    PubMed  CAS  Google Scholar 

  • Zhang X, Bolt M, Guertin MJ, Chen W, Zhang S, Cherrington BD, Slade DJ, Dreyton CJ, Subramanian V, Bicker KL et al (2012) Peptidylarginine deiminase 2-catalyzed histone H3 arginine 26 citrullination facilitates estrogen receptor alpha target gene activation. Proc Natl Acad Sci U S A 109:13331–13336

    PubMed  CAS  Google Scholar 

  • Zhang X, Gamble MJ, Stadler S, Cherrington BD, Causey CP, Thompson PR, Roberson MS, Kraus WL, Coonrod SA (2011) Genome-wide analysis reveals PADI4 cooperates with Elk-1 to activate c-fos expression in breast cancer cells. PLoS Genet 7:e1002112

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank all of our collaborators for years of support, especially Scott Coonrod (Cornell University), Lorne Hofseth (University of South Carolina), V. Michael Holers (University of Colorado), Mariana Kaplan (University of Michigan), and Marko Z. Radic (University of Tennessee Health Sciences Center). These have been productive and exciting collaborations that have greatly enhanced our understanding of PADs in disease. Funding supporting this work has been provided by NIH grants GM079357, CA151304, as well as the American College of Rheumatology, and institutional support from both USC and TSRI. Given the broad scope of this chapter we know that we have regrettably missed giving credit where credit it is due, and we apologize for this.

Author information

Authors and Affiliations

  1. Department of Chemistry, The Kellogg School of Graduate Studies, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33458, USA

    Venkataraman Subramanian, Daniel J. Slade & Paul R. Thompson

Authors
  1. Venkataraman Subramanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel J. Slade
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul R. Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul R. Thompson .

Editor information

Editors and Affiliations

  1. Department of Neurology, University of Alabama at Birmingham and The Birmingham Veterans Administration Medical Center, Birmingham, Alabama, USA

    Anthony P. Nicholas

  2. Bascom Palmer Eye Institute, University of Miami, MIAMI, Florida, USA

    Sanjoy K. Bhattacharya

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Subramanian, V., Slade, D.J., Thompson, P.R. (2014). Picking the PAD Lock: Chemical and Biological Approaches to Identify PAD Substrates and Inhibitors. In: Nicholas, A., Bhattacharya, S. (eds) Protein Deimination in Human Health and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8317-5_21

Download citation

Publish with us

Policies and ethics

Search

Navigation