Skip to main content

Advertisement

SpringerLink
Log in

PE-only/PE_PGRS proteins of Mycobacterium tuberculosis contain a conserved tetra-peptide sequence DEVS/DXXS that is a potential caspase-3 cleavage motif

  • Published:
Journal of Biosciences Aims and scope Submit manuscript

Abstract

Mycobacterium tuberculosis H37Rv is an intracellular pathogen responsible for causing tuberculosis in humans. The M. tuberculosis genome has been shown to contain a very large and unique family of PE proteins made of two sub-families: PE-only and PE_PGRS proteins. These two subtypes of proteins play a crucial role in the pathogenesis of the microbe. However, despite numerous investigations, the role of these proteins in disease development remains obscure. In this study, sequence analysis with a search for short conserved motifs revealed a conserved tetra-peptide motif DEVS/DXXS at the PE domain of almost every PE-only and PE_PGRS protein. The motif was found at a distance of 43–46 amino acids from the N-terminal of PE_PGRS proteins, and at a distance of between 35 and 82 amino acids of the PE-only proteins. As phosphorylation of the serine residue of this tetra-peptide could yield a motif similar to the caspase-3 binding recognition sequence DEVD/E, the region from a representative PE_PGRS protein (PE_PGRS45) was docked to human caspase-3. Strong interactions of only the protein containing the phosphorylated motif (DEVpS/DXXpS) to caspase-3 were observed. This suggested that the conserved DEVS/DXXS motif could have evolved for phosphorylation and subsequent recognition by caspase-3. These findings have important implications in unravelling the role of these PE proteins in mycobacterial infection.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Adindla S and Guruprasad L 2003 Sequence analysis corresponding to the PPE and PE proteins in Mycobacterium tuberculosis and other genomes. J. Biosci. 28 169–179

    Article  PubMed  CAS  Google Scholar 

  • Av-Gay Y and Everett M 2000 The eukaryotic-like Ser/Thr protein kinases of Mycobacterium tuberculosis. Trends Microbiol. 8 238–244

    Article  PubMed  CAS  Google Scholar 

  • Bachhawat N and Singh B 2007 Mycobacterial PE_PGRS proteins contain calcium-binding motifs with parallel beta-roll folds. Genomics Proteomics Bioinform. 5 236–241

    Article  CAS  Google Scholar 

  • Balcewicz-sablinska MK, Keane J, Kornfeld H and RemoldHG 1998 Pathogenic Mycobacterium tuberculosis evades apoptosis of host macrophages by release of TNF-R2, resulting in inactivation of TNF-alpha. J. Immunol. 161 2636–2641

    PubMed  CAS  Google Scholar 

  • Brennan MJ 2017 The enigmatic multi-gene family of mycobacteria and TB vaccination. Infect. Immun. 85 e00969–16

    Article  PubMed  PubMed Central  Google Scholar 

  • Bottai D and Brosch R 2009 Mycobacterial PE, PPE and ESX clusters: novel insights into the secretion of these most unusual protein families. Mol. Microbiol. 73 325–328

    Article  PubMed  CAS  Google Scholar 

  • Butler RE, Brodin P, Jang J, Jang M-S, Robertson BD, Gicquel Band Stewart GR 2012 The balance of apoptotic and necrotic cell death in Mycobacterium tuberculosis infected macrophages is not dependent on bacterial virulence. PLoS ONE 7 e47573

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cambier CJ, Falkow S and Ramakrishnan L 2014 Host evasion and exploitation schemes of Mycobacterium tuberculosis. Cell 159 1497–1509

    Article  PubMed  CAS  Google Scholar 

  • Chao J, Wong D, Zheng X, Poirier V, Bach H, Hmama Z and Av-Gay Y 2010 Protein kinase and phosphatase signaling in Mycobacterium tuberculosis physiology and pathogenesis. Biochim. Biophys. Acta 1804 620–627

    Article  PubMed  CAS  Google Scholar 

  • Clem RJ, Fechheimer M and Miller LK 1991 Prevention of apoptosis by a baculovirus gene during infection of insect cells. Science 254 1388–1390

    Article  PubMed  CAS  Google Scholar 

  • Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D et al. 1998 Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393 537–544 (erratum in: 1998 Nature 396 190)

  • Cozzone AJ 1998 Post-translational modification of proteins by reversible phosphorylation in prokaryotes. Biochimie 80 43–48

    Article  PubMed  CAS  Google Scholar 

  • Delogu G, Brennan MJ and Manganelli R 2017 PE and PPE genes: A tale of conservation and diversity. Adv. Exp. Med. Biol. 1019 191–207

    Article  PubMed  Google Scholar 

  • Domínguez DC, Guragain M and Patrauchan M 2015 Calcium binding proteins and calcium signalling in prokaryotes. Cell Calcium 57 151–165

    Article  PubMed  CAS  Google Scholar 

  • Edgar RC 2004 MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 32 1792–1797

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Edgar RC 2004 MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinf. 5 113

    Article  CAS  Google Scholar 

  • Fang B, Boross PI, Tozser J and Weber IT 2006 Structural and kinetic analysis of caspase-3 reveals role for s5 binding site in substrate recognition. J. Mol. Biol. 360 654–666

    Article  PubMed  CAS  Google Scholar 

  • Fratazzi C, Arbeit RD, Carini C and Remold HG 1997 Programmed cell death of Mycobacterium aviumser over 4-infected human macrophages prevents the mycobacteria from spreading and induces mycobacterial growth inhibition by freshly added, uninfected macrophages. J. Immunol. 158 4320–4327

    PubMed  CAS  Google Scholar 

  • Giorgi C, Baldassari F, Bononi A, Bonora M, Marchi ED and Marchi S 2012 Mitochondrial Ca(2+) and apoptosis. Cell Calcium 52 36–43

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Griffin JE, Gawronski JD, DeJesus MA, Ioerger TR, Akerley BJ and Sassetti CM 2011 High-resolution phenotypic profiling defines genes essential for mycobacterial growth and cholesterol catabolism. PLoS Pathog. 7 e1002251

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Keane J, Remold HG and Kornfeld H 2000 Virulent Mycobacterium tuberculosis strains evadeapoptosis of infected alveolar macrophages. J. Immunol. 164 2016–2020

    Article  PubMed  CAS  Google Scholar 

  • Kelley LA, Mezulis S, Yates CM, Wass MN and Sternberg M JE 2015 The Phyre2 web portal for protein modelling, prediction and analysis. Nat. Protocol. 10 845–858

    Article  CAS  Google Scholar 

  • Krebs EG and Fischer EH1956 The phosphorylase b to a converting enzyme of rabbit skeletal muscle. Biochim. Biophys. Acta 20 150–157

    Article  PubMed  CAS  Google Scholar 

  • Lew JM, Kapopoulou A, Jones LM and Cole ST 2011 TubercuList—10 years after. Tuberculosis 1 1–7

    Article  Google Scholar 

  • Lien S, Pastor R, Sutherlin D and Lowman HB 2004 A substrate-phage approach for investigating caspase specificity. Protein J. 23 413–425

    Article  PubMed  CAS  Google Scholar 

  • Molmeret M, Zink SD, Han L, Abu-Zant A, Asari R, Bitar DM and Abu Kwaik Y 2004 Activation of caspase-3 by the Dot/Icm virulence system is essential for arrestedbiogenesis of the Legionella-containing phagosome. Cell Microbiol. 6 33–48

    Article  PubMed  CAS  Google Scholar 

  • Pierce BG, Wiehe K, Hwang H, Kim BH, Vreven T and Weng Z 2014 ZDOCK server: Interactive docking prediction of protein-protein complexes and symmetric multimers. Bioinformatics 30 1771–1773

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Poreba M, Strózyk A, Salvesen GS and Drag M 2013 Caspase substrates and inhibitors. Cold Spring Harb. Perspect. Biol. 5 a008680

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ramakrishnan L, Federspiel NA and Falkow S 2000 Granuloma-specific expression of Mycobacterium virulence proteins from the glycine-rich PE-PGRS family. Science 288 1436–1439

    Article  PubMed  CAS  Google Scholar 

  • Ribet D and Cossart P 2010 Pathogen-mediated posttranslational modifications: A re-emerging field. Cell 143 694–702

    Article  PubMed  CAS  Google Scholar 

  • Richard A and Tulasne D 2012 Caspase cleavage of viral proteins, another way for viruses to make the best of apoptosis. Cell Death Dis. 3 e277

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Richard-Greenblatt M and Av-Gay Y 2017 Epigenetic phosphorylation control of Mycobacterium tuberculosis infection and persistence. Microbiol. Spectr. 5 https://doi.org/10.1128/microbiolspec.tbtb2-0005-2015

    Article  PubMed  Google Scholar 

  • Riendeau CJ and Kornfeld H 2003 THP-1 cell apoptosis in response to Mycobacterial infection. Infect. Immun. 71 254–259

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Russell DG 2011 Mycobacterium tuberculosis and the intimate discourse of a chronic infection. Immunol. Rev. 240 252–268

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sassetti CM, Boyd DH and Rubin EJ 2003 Genes required for mycobacterial growth defined by high density mutagenesis. Mol. Microbiol. 48 77–84

    Article  PubMed  CAS  Google Scholar 

  • Schaaf K, Smith SR, Duverger A, Wagner F, Wolschendorf F, Westfall AO, Kutsch O and Sun J 2017 Mycobacterium tuberculosis exploits the PPM1A signaling pathway to block host macrophage apoptosis. Sci. Rep. 7 42101

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Seaman JE, Julien O, Lee PS, Rettenmaier TJ, Thomsen ND amd Wells JA 2016 Cacidases: caspases can cleave after aspartate, glutamate and phosphoserine residues. Cell Death Differ. 23 1717–1726

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Srikanth CV, Wall DM, Maldonado-Contreras A, Shi H, Zhou D, Demma Z, Mumy KL and McCormick BA 2010 Salmonella pathogenesis and processing of secreted effectors by caspase-3. Science 330 390–393

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Timmer JC and Salvesen GS 2007 Caspase substrates. Cell Death Differ. 14 66–72

    Article  PubMed  CAS  Google Scholar 

  • Tiwari BM, Kannan N, Vemu L and Raghunand TR 2012 The Mycobacterium tuberculosis PE proteins Rv0285 and Rv1386 modulate innate immunity and mediate bacillary survival in macrophages. PLoS ONE 7 e51686

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • van der Wel N, Hava D, Houben D, Fluitsma D, van Zon M, Pierson J, Brenner M and Peters PJ 2007 M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell 129 1287–1298

    Article  PubMed  CAS  Google Scholar 

  • Vergne I, Chua J, Lee HH, Lucas M, Belisle J and Deretic V 2005 Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA 102 4033–4038

    Article  PubMed  CAS  Google Scholar 

  • Xue D and Horvitz HR 1995 Inhibition of the Caenorhabditis elegans cell-death protease CED-3 by a CED-3 cleavage site in baculovirus p35 protein. Nature 377 248–251

    Article  PubMed  CAS  Google Scholar 

  • Yeruva VC, Kulkarni A, Khandelwal R, Sharma Y and Raghunand TR 2016 The PE_PGRS proteins of Mycobacterium tuberculosis are Ca(2+) binding mediators of host-pathogen interaction. Biochemistry 55 4675–4687

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

I am indebted to Pankaj Kumar, Johns Hopkins University School of Medicine, Baltimore, USA, for his generous help in making the PE_PGRS45 human caspase-3 structural model. I thank Arunaloke Chakrabarti, PGIMER, Chandigarh, and Samir Brahmachari, 1G1B, Delhi for their encouragement, and Pradip Sen, IMTech, Chandigarh, and Anand K Bachhawat, IISER-Mohali, for their critical and helpful comments.

Author information

Authors and Affiliations

  1. 1079/2, HIG Complex, Sector 39B, Chandigarh, 160036, India

    Nandita Bachhawat

Authors
  1. Nandita Bachhawat
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nandita Bachhawat.

Additional information

Communicated by B JAGADEESHWAR RAO.

Corresponding editor: B Jagadeeshwar Rao

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 40 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bachhawat, N. PE-only/PE_PGRS proteins of Mycobacterium tuberculosis contain a conserved tetra-peptide sequence DEVS/DXXS that is a potential caspase-3 cleavage motif. J Biosci 43, 597–604 (2018). https://doi.org/10.1007/s12038-018-9775-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12038-018-9775-0

Keywords

Search

Navigation