PTPA_MYCTU
ID PTPA_MYCTU Reviewed; 163 AA.
AC P9WIA1; L0TAK9; P65716; Q10507;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 48.
DE RecName: Full=Low molecular weight protein-tyrosine phosphatase A {ECO:0000303|PubMed:16258834};
DE Short=LMW-PTP {ECO:0000303|PubMed:22888002};
DE Short=PTPase {ECO:0000305};
DE EC=3.1.3.48 {ECO:0000269|PubMed:10986245, ECO:0000269|PubMed:12066895, ECO:0000269|PubMed:17975835, ECO:0000269|PubMed:23102706, ECO:0000269|PubMed:32142609};
DE AltName: Full=Low molecular weight tyrosine phosphatase PtpA {ECO:0000303|PubMed:12066895};
DE AltName: Full=MPtpA {ECO:0000303|PubMed:10986245};
GN Name=ptpA {ECO:0000303|PubMed:12066895};
GN Synonyms=mptpA {ECO:0000303|PubMed:10986245}; OrderedLocusNames=Rv2234;
GN ORFNames=MTCY427.15;
OS Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83332;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=9634230; DOI=10.1038/31159;
RA Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA Barrell B.G.;
RT "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT genome sequence.";
RL Nature 393:537-544(1998).
RN [2]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION,
RP AND MUTAGENESIS OF CYS-11.
RC STRAIN=H37Rv;
RX PubMed=10986245; DOI=10.1128/jb.182.19.5425-5432.2000;
RA Koul A., Choidas A., Treder M., Tyagi A.K., Drlica K., Singh Y.,
RA Ullrich A.;
RT "Cloning and characterization of secretory tyrosine phosphatases of
RT Mycobacterium tuberculosis.";
RL J. Bacteriol. 182:5425-5432(2000).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR
RP LOCATION, AND INDUCTION.
RC STRAIN=H37Rv;
RX PubMed=12066895; DOI=10.1016/s0923-2508(02)01309-8;
RA Cowley S.C., Babakaiff R., Av-Gay Y.;
RT "Expression and localization of the Mycobacterium tuberculosis protein
RT tyrosine phosphatase PtpA.";
RL Res. Microbiol. 153:233-241(2002).
RN [4]
RP FUNCTION IN VIRULENCE.
RC STRAIN=H37Rv;
RX PubMed=16085396; DOI=10.1016/j.resmic.2005.05.013;
RA Castandet J., Prost J.F., Peyron P., Astarie-Dequeker C., Anes E.,
RA Cozzone A.J., Griffiths G., Maridonneau-Parini I.;
RT "Tyrosine phosphatase MptpA of Mycobacterium tuberculosis inhibits
RT phagocytosis and increases actin polymerization in macrophages.";
RL Res. Microbiol. 156:1005-1013(2005).
RN [5]
RP BIOTECHNOLOGY.
RX PubMed=16196020; DOI=10.1002/cbic.200500171;
RA Manger M., Scheck M., Prinz H., von Kries J.P., Langer T., Saxena K.,
RA Schwalbe H., Fuerstner A., Rademann J., Waldmann H.;
RT "Discovery of Mycobacterium tuberculosis protein tyrosine phosphatase A
RT (MptpA) inhibitors based on natural products and a fragment-based
RT approach.";
RL ChemBioChem 6:1749-1753(2005).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL
RP PROPERTIES, ACTIVE SITE, AND MUTAGENESIS OF CYS-11; ARG-17 AND ASP-126.
RX PubMed=17975835; DOI=10.1002/prot.21816;
RA Madhurantakam C., Chavali V.R., Das A.K.;
RT "Analyzing the catalytic mechanism of MPtpA: a low molecular weight protein
RT tyrosine phosphatase from Mycobacterium tuberculosis through site-directed
RT mutagenesis.";
RL Proteins 71:706-714(2008).
RN [7]
RP FUNCTION IN VIRULENCE, INTERACTION WITH HUMAN VPS33B, SUBCELLULAR LOCATION,
RP DISRUPTION PHENOTYPE, AND MUTAGENESIS OF CYS-11; ARG-17 AND ASP-126.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=18474358; DOI=10.1016/j.chom.2008.03.008;
RA Bach H., Papavinasasundaram K.G., Wong D., Hmama Z., Av-Gay Y.;
RT "Mycobacterium tuberculosis virulence is mediated by PtpA dephosphorylation
RT of human vacuolar protein sorting 33B.";
RL Cell Host Microbe 3:316-322(2008).
RN [8]
RP DISRUPTION PHENOTYPE.
RX PubMed=18752626; DOI=10.1111/j.1574-6968.2008.01309.x;
RA Grundner C., Cox J.S., Alber T.;
RT "Protein tyrosine phosphatase PtpA is not required for Mycobacterium
RT tuberculosis growth in mice.";
RL FEMS Microbiol. Lett. 287:181-184(2008).
RN [9]
RP PHOSPHORYLATION AT TYR-128 AND TYR-129, AND MUTAGENESIS OF TYR-67; TYR-128
RP AND TYR-129.
RX PubMed=19366344; DOI=10.1042/bj20090478;
RA Bach H., Wong D., Av-Gay Y.;
RT "Mycobacterium tuberculosis PtkA is a novel protein tyrosine kinase whose
RT substrate is PtpA.";
RL Biochem. J. 420:155-160(2009).
RN [10]
RP BIOTECHNOLOGY.
RX PubMed=19889539; DOI=10.1016/j.bmcl.2009.10.090;
RA Rawls K.A., Lang P.T., Takeuchi J., Imamura S., Baguley T.D., Grundner C.,
RA Alber T., Ellman J.A.;
RT "Fragment-based discovery of selective inhibitors of the Mycobacterium
RT tuberculosis protein tyrosine phosphatase PtpA.";
RL Bioorg. Med. Chem. Lett. 19:6851-6854(2009).
RN [11]
RP S-NITROSYLATION AT CYS-53, ACTIVITY REGULATION, AND MUTAGENESIS OF CYS-11;
RP CYS-16 AND CYS-53.
RX PubMed=20830431; DOI=10.1039/c0cc01704c;
RA Ecco G., Vernal J., Razzera G., Martins P.A., Matiollo C., Terenzi H.;
RT "Mycobacterium tuberculosis tyrosine phosphatase A (PtpA) activity is
RT modulated by S-nitrosylation.";
RL Chem. Commun. (Camb.) 46:7501-7503(2010).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21969609; DOI=10.1074/mcp.m111.011627;
RA Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B., Yadav A.K.,
RA Shrivastava P., Marimuthu A., Anand S., Sundaram H., Kingsbury R.,
RA Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., Katoch K., Katoch V.M.,
RA Kumar P., Chaerkady R., Ramachandran S., Dash D., Pandey A.;
RT "Proteogenomic analysis of Mycobacterium tuberculosis by high resolution
RT mass spectrometry.";
RL Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN [13]
RP FUNCTION IN VIRULENCE, INTERACTION WITH HOST V-ATPASE, AND MUTAGENESIS OF
RP ASP-126 AND LEU-146.
RX PubMed=22087003; DOI=10.1073/pnas.1109201108;
RA Wong D., Bach H., Sun J., Hmama Z., Av-Gay Y.;
RT "Mycobacterium tuberculosis protein tyrosine phosphatase (PtpA) excludes
RT host vacuolar-H+-ATPase to inhibit phagosome acidification.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:19371-19376(2011).
RN [14]
RP BIOTECHNOLOGY.
RX PubMed=22136336; DOI=10.1021/jm2012062;
RA Chiaradia L.D., Martins P.G., Cordeiro M.N., Guido R.V., Ecco G.,
RA Andricopulo A.D., Yunes R.A., Vernal J., Nunes R.J., Terenzi H.;
RT "Synthesis, biological evaluation, and molecular modeling of chalcone
RT derivatives as potent inhibitors of Mycobacterium tuberculosis protein
RT tyrosine phosphatases (PtpA and PtpB).";
RL J. Med. Chem. 55:390-402(2012).
RN [15]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL
RP PROPERTIES, AND S-NITROSYLATION AT CYS-53.
RX PubMed=23102706; DOI=10.1016/j.bbapap.2012.10.007;
RA Matiollo C., Ecco G., Menegatti A.C., Razzera G., Vernal J., Terenzi H.;
RT "S-nitrosylation of Mycobacterium tuberculosis tyrosine phosphatase A
RT (PtpA) induces its structural instability.";
RL Biochim. Biophys. Acta 1834:191-196(2013).
RN [16]
RP FUNCTION IN VIRULENCE, AND INTERACTION WITH HOST GSK-3 ALPHA.
RX PubMed=25187516; DOI=10.1074/jbc.m114.582502;
RA Poirier V., Bach H., Av-Gay Y.;
RT "Mycobacterium tuberculosis promotes anti-apoptotic activity of the
RT macrophage by PtpA protein-dependent dephosphorylation of host GSK3alpha.";
RL J. Biol. Chem. 289:29376-29385(2014).
RN [17]
RP ACTIVITY REGULATION, PHOSPHORYLATION AT THR-45; TYR-128 AND TYR-129, AND
RP MUTAGENESIS OF THR-8; THR-12; THR-41; THR-45; THR-69; THR-78; THR-119;
RP TYR-128 AND TYR-129.
RX PubMed=25535696; DOI=10.1016/j.febslet.2014.12.015;
RA Zhou P., Li W., Wong D., Xie J., Av-Gay Y.;
RT "Phosphorylation control of protein tyrosine phosphatase A activity in
RT Mycobacterium tuberculosis.";
RL FEBS Lett. 589:326-331(2015).
RN [18]
RP FUNCTION IN VIRULENCE, INTERACTION WITH HOST UBIQUITIN AND HOST TAB3, AND
RP MUTAGENESIS OF ALA-140.
RX PubMed=25642820; DOI=10.1038/ni.3096;
RA Wang J., Li B.X., Ge P.P., Li J., Wang Q., Gao G.F., Qiu X.B., Liu C.H.;
RT "Mycobacterium tuberculosis suppresses innate immunity by coopting the host
RT ubiquitin system.";
RL Nat. Immunol. 16:237-245(2015).
RN [19]
RP FUNCTION.
RX PubMed=25743628; DOI=10.1038/srep08819;
RA Margenat M., Labandera A.M., Gil M., Carrion F., Purificacao M.,
RA Razzera G., Portela M.M., Obal G., Terenzi H., Pritsch O., Duran R.,
RA Ferreira A.M., Villarino A.;
RT "New potential eukaryotic substrates of the mycobacterial protein tyrosine
RT phosphatase PtpA: hints of a bacterial modulation of macrophage
RT bioenergetics state.";
RL Sci. Rep. 5:8819-8819(2015).
RN [20]
RP FUNCTION IN VIRULENCE, AND INTERACTION WITH HOST TRIM27.
RX PubMed=27698396; DOI=10.1038/srep34827;
RA Wang J., Teng J.L., Zhao D., Ge P., Li B., Woo P.C., Liu C.H.;
RT "The ubiquitin ligase TRIM27 functions as a host restriction factor
RT antagonized by Mycobacterium tuberculosis PtpA during mycobacterial
RT infection.";
RL Sci. Rep. 6:34827-34827(2016).
RN [21]
RP FUNCTION IN VIRULENCE, DNA-BINDING, AND SUBCELLULAR LOCATION.
RX PubMed=28811474; DOI=10.1038/s41467-017-00279-z;
RA Wang J., Ge P., Qiang L., Tian F., Zhao D., Chai Q., Zhu M., Zhou R.,
RA Meng G., Iwakura Y., Gao G.F., Liu C.H.;
RT "The mycobacterial phosphatase PtpA regulates the expression of host genes
RT and promotes cell proliferation.";
RL Nat. Commun. 8:244-244(2017).
RN [22]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL
RP PROPERTIES, AND DOMAIN.
RX PubMed=32142609; DOI=10.1021/acs.biochem.0c00059;
RA Stefan A., Dal Piaz F., Girella A., Hochkoeppler A.;
RT "Substrate activation of the low-molecular weight protein tyrosine
RT phosphatase from Mycobacterium tuberculosis.";
RL Biochemistry 59:1137-1148(2020).
RN [23]
RP REVIEW.
RX PubMed=23084287; DOI=10.1016/j.tim.2012.09.002;
RA Wong D., Chao J.D., Av-Gay Y.;
RT "Mycobacterium tuberculosis-secreted phosphatases: from pathogenesis to
RT targets for TB drug development.";
RL Trends Microbiol. 21:100-109(2013).
RN [24] {ECO:0007744|PDB:1U2P, ECO:0007744|PDB:1U2Q}
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS), AND ACTIVE SITE.
RC STRAIN=H37Rv;
RX PubMed=15743966; DOI=10.1128/jb.187.6.2175-2181.2005;
RA Madhurantakam C., Rajakumara E., Mazumdar P.A., Saha B., Mitra D.,
RA Wiker H.G., Sankaranarayanan R., Das A.K.;
RT "Crystal structure of low-molecular-weight protein tyrosine phosphatase
RT from Mycobacterium tuberculosis at 1.9-A resolution.";
RL J. Bacteriol. 187:2175-2181(2005).
RN [25]
RP STRUCTURE BY NMR.
RX PubMed=16258834; DOI=10.1007/s10858-005-2718-8;
RA Saxena K., Elshorst B., Berk H., Betz M., Grimme S., Langer T.,
RA Pescatore B., Schieborr U., Vogtherr M., Schwalbe H.;
RT "Backbone NMR assignment of the low-molecular-weight protein tyrosine
RT phosphatase (MPtpA) from Mycobacterium tuberculosis.";
RL J. Biomol. NMR 33:136-136(2005).
RN [26] {ECO:0007744|PDB:2LUO}
RP STRUCTURE BY NMR, PHOSPHORYLATION AT TYR-128 AND TYR-129, AND DOMAIN.
RX PubMed=22888002; DOI=10.1074/jbc.m112.399261;
RA Stehle T., Sreeramulu S., Lohr F., Richter C., Saxena K., Jonker H.R.,
RA Schwalbe H.;
RT "The apo-structure of the low molecular weight protein-tyrosine phosphatase
RT A (MptpA) from Mycobacterium tuberculosis allows for better target-specific
RT drug development.";
RL J. Biol. Chem. 287:34569-34582(2012).
CC -!- FUNCTION: Key virulence factor required for mycobacterial survival
CC within host macrophages (PubMed:16085396, PubMed:18474358,
CC PubMed:22087003, PubMed:25187516, PubMed:25642820, PubMed:27698396).
CC Exhibits protein tyrosine phosphatase activity (PubMed:10986245,
CC PubMed:12066895, PubMed:17975835, PubMed:23102706, PubMed:25187516,
CC PubMed:32142609). Shows no detectable activity towards substrates
CC containing phosphoserine/threonine residues (PubMed:10986245,
CC PubMed:12066895). {ECO:0000269|PubMed:10986245,
CC ECO:0000269|PubMed:12066895, ECO:0000269|PubMed:16085396,
CC ECO:0000269|PubMed:17975835, ECO:0000269|PubMed:18474358,
CC ECO:0000269|PubMed:22087003, ECO:0000269|PubMed:23102706,
CC ECO:0000269|PubMed:25187516, ECO:0000269|PubMed:25642820,
CC ECO:0000269|PubMed:27698396, ECO:0000269|PubMed:32142609}.
CC -!- FUNCTION: Supports mycobacteria survival during infection by modulation
CC of the phagosome maturation and modulation of the normal host signaling
CC pathways, including host innate immune responses and cell apoptosis
CC (PubMed:18474358, PubMed:22087003, PubMed:25187516, PubMed:25642820,
CC PubMed:27698396). Affects the phagocytosis process by preventing
CC phagosome acidification and maturation in the macrophage
CC (PubMed:22087003, PubMed:16085396, PubMed:18474358). This inhibition
CC depends on both PtpA phosphatase activity and its ability to bind to
CC host vacuolar-H(+)-ATPase (V-ATPase) machinery (PubMed:22087003).
CC Enters into the host cytosol and binds to subunit H of the human V-
CC ATPase machinery to block V-ATPase trafficking and phagosome
CC acidification (PubMed:22087003). Dephosphorylates and inactivates host
CC VPS33B protein, which inhibits phagosome maturation, fusion with the
CC lysosome and promotes bacteria survival (PubMed:18474358,
CC PubMed:22087003). Dephosphorylation of VPS33B requires interaction of
CC PtpA with host V-ATPase and ubiquitin (PubMed:22087003,
CC PubMed:25642820). Binding to host ubiquitin also leads to the
CC dephosphorylation of phosphorylated Jnk and MAPK p38, leading to
CC suppression of innate immunity (PubMed:25642820). Dephosphorylates host
CC GSK-3 alpha on Tyr-279, which leads to modulation of GSK-3 alpha anti-
CC apoptotic activity, promoting pathogen survival early during infection
CC (PubMed:25187516). In vitro, dephosphorylates two subunits of the
CC trifunctional enzyme TFP (ECHA/ ECHB), which means that it may also
CC affect pathways involved in cell energy metabolism (PubMed:25743628).
CC Furthermore, blocks innate immune system responses mediated by the host
CC adapter TAB3 and dependent on NF-kappa-B by competitively binding the
CC ubiquitin-interacting domain of TAB3, in a phosphatase activity-
CC independent manner (PubMed:25642820). Antagonizes TRIM27-promoted
CC JNK/p38 MAPK pathway activation and cell apoptosis through
CC competitively binding to the RING domain of TRIM27 (PubMed:27698396).
CC In addition, PtpA enters the nucleus of host cells and regulates the
CC expression of several host genes, some of which are known to be
CC involved in host innate immunity or in cell proliferation and
CC migration, either by directly binding to the promoters of its target
CC genes, or in an indirect manner (PubMed:28811474). In vitro, can bind
CC directly to the promoter region of GADD45A, a gene encoding a protein
CC involved in cell division, cell death and senescence, and DNA-damage
CC repair (PubMed:28811474). {ECO:0000269|PubMed:16085396,
CC ECO:0000269|PubMed:18474358, ECO:0000269|PubMed:22087003,
CC ECO:0000269|PubMed:25187516, ECO:0000269|PubMed:25642820,
CC ECO:0000269|PubMed:25743628, ECO:0000269|PubMed:27698396,
CC ECO:0000269|PubMed:28811474}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O-phospho-L-tyrosyl-[protein] = L-tyrosyl-[protein] +
CC phosphate; Xref=Rhea:RHEA:10684, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620; EC=3.1.3.48;
CC Evidence={ECO:0000269|PubMed:10986245, ECO:0000269|PubMed:12066895,
CC ECO:0000269|PubMed:17975835, ECO:0000269|PubMed:23102706,
CC ECO:0000269|PubMed:32142609};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:10685;
CC Evidence={ECO:0000269|PubMed:10986245, ECO:0000269|PubMed:12066895,
CC ECO:0000269|PubMed:17975835, ECO:0000269|PubMed:23102706,
CC ECO:0000269|PubMed:32142609};
CC -!- ACTIVITY REGULATION: Phosphatase activity is stimulated by
CC phosphorylation (PubMed:25535696). Inhibited by sodium molybdate,
CC sodium orthovanadate and sodium tungstate (PubMed:10986245,
CC PubMed:17975835). Inhibited by S-nitrosylation (PubMed:20830431,
CC PubMed:23102706). Subjected to substrate activation, triggered by pNPP
CC or by phosphotyrosine. Is also activated by phosphoserine, with serine
CC being ineffective in enhancing PtpA activity (PubMed:32142609).
CC {ECO:0000269|PubMed:10986245, ECO:0000269|PubMed:17975835,
CC ECO:0000269|PubMed:20830431, ECO:0000269|PubMed:23102706,
CC ECO:0000269|PubMed:25535696, ECO:0000269|PubMed:32142609}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.402 mM for free O-phosphotyrosine {ECO:0000269|PubMed:12066895};
CC KM=5.4 mM for phosphotyrosine {ECO:0000269|PubMed:32142609};
CC KM=0.131 mM for O-phosphotyrosine peptide
CC {ECO:0000269|PubMed:12066895};
CC KM=0.026 mM for myelin basic protein {ECO:0000269|PubMed:12066895};
CC KM=3.21 mM for pNPP (at pH 5.0) {ECO:0000269|PubMed:17975835};
CC KM=2.96 mM for pNPP (at pH 6.0) {ECO:0000269|PubMed:17975835};
CC KM=2.86 mM for pNPP (at pH 7.0) {ECO:0000269|PubMed:17975835};
CC KM=1.44 mM for pNPP {ECO:0000269|PubMed:23102706};
CC KM=6.1 mM for pNPP {ECO:0000269|PubMed:32142609};
CC KM=1.33 mM for pNPP (in the presence of S-nitrosoglutathione)
CC {ECO:0000269|PubMed:23102706};
CC Vmax=1.688 umol/min/mg enzyme with free O-phosphotyrosine as
CC substrate {ECO:0000269|PubMed:12066895};
CC Vmax=0.095 umol/min/mg enzyme with O-phosphotyrosine peptide as
CC substrate {ECO:0000269|PubMed:12066895};
CC Vmax=0.03 umol/min/mg enzyme with myelin basic protein as substrate
CC {ECO:0000269|PubMed:12066895};
CC Vmax=41.15 umol/min/mg enzyme with pNPP as substrate
CC {ECO:0000269|PubMed:23102706};
CC Vmax=20.12 umol/min/mg enzyme with pNPP as substrate (in the presence
CC of S-nitrosoglutathione) {ECO:0000269|PubMed:23102706};
CC Note=kcat is 12.6 sec(-1) with pNPP as substrate at pH 5.0. kcat is
CC 1313 sec(-1) with pNPP as substrate at pH 6.0. kcat is 1334 sec(-1)
CC with pNPP as substrate at pH 7.0 (PubMed:17975835). kcat is 13.73
CC sec(-1) with pNPP as substrate. kcat is 6.71 with pNPP as substrate
CC (in the presence of S-nitrosoglutathione) (PubMed:23102706). kcat is
CC 0.87 sec(-1) with pNPP as substrate. kcat is 0.69 sec(-1) with
CC phosphotyrosine as substrate (PubMed:32142609).
CC {ECO:0000269|PubMed:17975835, ECO:0000269|PubMed:23102706,
CC ECO:0000269|PubMed:32142609};
CC -!- SUBUNIT: Interacts with the host VPS33B protein in macrophages
CC (PubMed:18474358). Interacts with subunit H of host V-ATPase
CC (PubMed:22087003). Interacts with host GSK-3 alpha (PubMed:25187516).
CC Interacts with host ubiquitin and host adapter TAB3 (PubMed:25642820).
CC Interacts with host TRIM27 (PubMed:27698396).
CC {ECO:0000269|PubMed:18474358, ECO:0000269|PubMed:22087003,
CC ECO:0000269|PubMed:25187516, ECO:0000269|PubMed:25642820,
CC ECO:0000269|PubMed:27698396}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:10986245,
CC ECO:0000269|PubMed:12066895, ECO:0000269|PubMed:18474358}. Host
CC cytoplasmic vesicle, host phagosome {ECO:0000269|PubMed:18474358}. Host
CC cytoplasm {ECO:0000269|PubMed:18474358, ECO:0000269|PubMed:28811474}.
CC Host nucleus {ECO:0000269|PubMed:28811474}. Note=Translocates into the
CC host cytosol by crossing the host phagosomal membrane during human
CC macrophage infection. Colocalizes with host VPS33B in macrophage
CC cytosol and associates with phagosomes. {ECO:0000269|PubMed:18474358}.
CC -!- INDUCTION: Up-regulated upon infection of human monocytes.
CC {ECO:0000269|PubMed:12066895}.
CC -!- DOMAIN: The activation most likely occurs via a reversible
CC conformational rearrangement of the enzyme, leading to a catalytically
CC competent form (PubMed:32142609). Both the P- and D-loop form part of
CC the binding interface (PubMed:22888002). {ECO:0000269|PubMed:22888002,
CC ECO:0000269|PubMed:32142609}.
CC -!- PTM: Phosphorylated on tyrosines 128 and 129 by PtkA (PubMed:19366344,
CC PubMed:22888002, PubMed:25535696). Both Tyr-128 and Tyr-129 together
CC are essential for PtpA phosphatase activity (PubMed:25535696). In
CC vitro, can be phosphorylated by several eukaryotic-like Ser/Thr protein
CC kinases, such as protein kinase A (PknA), which phosphorylates PtpA at
CC Thr-45 and increases its activity (PubMed:25535696).
CC {ECO:0000269|PubMed:19366344, ECO:0000269|PubMed:22888002,
CC ECO:0000269|PubMed:25535696}.
CC -!- PTM: S-nitrosylation at Cys-53 decreases activity (PubMed:20830431).
CC Modification does not affect substrate affinity, but decreases protein
CC thermal stability and promotes a local effect in the surroundings of
CC the Cys-53 residue, which interferes in both protein stability and
CC function (PubMed:23102706). {ECO:0000269|PubMed:20830431,
CC ECO:0000269|PubMed:23102706}.
CC -!- DISRUPTION PHENOTYPE: Deletion mutant is attenuated in human
CC macrophages (PubMed:18474358). The mutant is not defective when grown
CC in vitro and also shows no growth defect in a mouse infection model
CC (PubMed:18752626). {ECO:0000269|PubMed:18474358,
CC ECO:0000269|PubMed:18752626}.
CC -!- BIOTECHNOLOGY: The important role played by PtpA in virulence makes it
CC a highly promising target for the treatment of tuberculosis infections.
CC Several classes of potent inhibitors have been developed and studied to
CC date. Drug candidates include, among others, stevastelins,
CC roseophilins, prodigiosins, hydroxypyrrole benzoic acids,
CC difluoromethylphosphonic acid (DFMP) and chalcone derivatives.
CC {ECO:0000269|PubMed:16196020, ECO:0000269|PubMed:19889539,
CC ECO:0000269|PubMed:22136336}.
CC -!- SIMILARITY: Belongs to the low molecular weight phosphotyrosine protein
CC phosphatase family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AL123456; CCP45013.1; -; Genomic_DNA.
DR PIR; F70777; F70777.
DR RefSeq; NP_216750.1; NC_000962.3.
DR RefSeq; WP_003411510.1; NZ_NVQJ01000008.1.
DR PDB; 1U2P; X-ray; 1.90 A; A=1-163.
DR PDB; 1U2Q; X-ray; 2.50 A; A=1-163.
DR PDB; 2LUO; NMR; -; A=1-163.
DR PDBsum; 1U2P; -.
DR PDBsum; 1U2Q; -.
DR PDBsum; 2LUO; -.
DR AlphaFoldDB; P9WIA1; -.
DR BMRB; P9WIA1; -.
DR SMR; P9WIA1; -.
DR BioGRID; 4356823; 8.
DR STRING; 83332.Rv2234; -.
DR BindingDB; P9WIA1; -.
DR ChEMBL; CHEMBL4542; -.
DR PaxDb; P9WIA1; -.
DR DNASU; 887373; -.
DR GeneID; 45426212; -.
DR GeneID; 887373; -.
DR KEGG; mtu:Rv2234; -.
DR TubercuList; Rv2234; -.
DR eggNOG; COG0394; Bacteria.
DR OMA; TGSWHVG; -.
DR PhylomeDB; P9WIA1; -.
DR BRENDA; 3.1.3.48; 3445.
DR Reactome; R-HSA-9635465; Suppression of apoptosis.
DR Reactome; R-HSA-9636383; Prevention of phagosomal-lysosomal fusion.
DR Reactome; R-HSA-9636467; Blockage of phagosome acidification.
DR Reactome; R-HSA-9637628; Modulation by Mtb of host immune system.
DR PRO; PR:P9WIA1; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; IDA:MTBBASE.
DR GO; GO:0044161; C:host cell cytoplasmic vesicle; IEA:UniProtKB-SubCell.
DR GO; GO:0042025; C:host cell nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR GO; GO:0004725; F:protein tyrosine phosphatase activity; IDA:MTBBASE.
DR GO; GO:0052025; P:modification by symbiont of host cell membrane; IMP:MTBBASE.
DR GO; GO:0033668; P:negative regulation by symbiont of host apoptotic process; TAS:Reactome.
DR GO; GO:0006470; P:protein dephosphorylation; IDA:MTBBASE.
DR GO; GO:0052083; P:suppression by symbiont of host cell-mediated immune response; IMP:MTBBASE.
DR InterPro; IPR023485; Ptyr_pPase.
DR InterPro; IPR036196; Ptyr_pPase_sf.
DR InterPro; IPR017867; Tyr_phospatase_low_mol_wt.
DR Pfam; PF01451; LMWPc; 1.
DR PRINTS; PR00719; LMWPTPASE.
DR SMART; SM00226; LMWPc; 1.
DR SUPFAM; SSF52788; SSF52788; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Host cytoplasm; Host cytoplasmic vesicle; Host nucleus;
KW Hydrolase; Phosphoprotein; Protein phosphatase; Reference proteome;
KW S-nitrosylation; Secreted; Virulence.
FT CHAIN 1..163
FT /note="Low molecular weight protein-tyrosine phosphatase A"
FT /id="PRO_0000046567"
FT ACT_SITE 11
FT /note="Nucleophile"
FT /evidence="ECO:0000305|PubMed:15743966,
FT ECO:0000305|PubMed:17975835"
FT ACT_SITE 17
FT /evidence="ECO:0000305|PubMed:15743966,
FT ECO:0000305|PubMed:17975835"
FT ACT_SITE 126
FT /note="Proton donor"
FT /evidence="ECO:0000305|PubMed:15743966,
FT ECO:0000305|PubMed:17975835"
FT MOD_RES 45
FT /note="Phosphothreonine; by PknA"
FT /evidence="ECO:0000269|PubMed:25535696"
FT MOD_RES 53
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000269|PubMed:20830431,
FT ECO:0000269|PubMed:23102706"
FT MOD_RES 128
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:19366344,
FT ECO:0000269|PubMed:22888002, ECO:0000269|PubMed:25535696"
FT MOD_RES 129
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:19366344,
FT ECO:0000269|PubMed:22888002, ECO:0000269|PubMed:25535696"
FT MUTAGEN 8
FT /note="T->A: No change in phosphatase activity."
FT /evidence="ECO:0000269|PubMed:25535696"
FT MUTAGEN 11
FT /note="C->A: Loss of phosphatase activity. Inhibits its
FT dephosphorylation activity on human VPS33B. Reduces its
FT effect on phagolysosome fusion in infected macrophages.
FT Does not affect nitrosylation."
FT /evidence="ECO:0000269|PubMed:18474358,
FT ECO:0000269|PubMed:20830431"
FT MUTAGEN 11
FT /note="C->S: Loss of phosphatase activity."
FT /evidence="ECO:0000269|PubMed:10986245,
FT ECO:0000269|PubMed:17975835"
FT MUTAGEN 12
FT /note="T->A: Strong decrease in phosphatase activity."
FT /evidence="ECO:0000269|PubMed:25535696"
FT MUTAGEN 16
FT /note="C->A: Does not affect nitrosylation. 80% decrease in
FT phosphatase activity."
FT /evidence="ECO:0000269|PubMed:20830431"
FT MUTAGEN 17
FT /note="R->A: Loss of phosphatase activity. Inhibits its
FT dephosphorylation activity on human VPS33B. 36-fold
FT decrease in catalytic efficiency toward pNPP at pH 7.0."
FT /evidence="ECO:0000269|PubMed:17975835,
FT ECO:0000269|PubMed:18474358"
FT MUTAGEN 41
FT /note="T->A: Slight decrease in phosphatase activity."
FT /evidence="ECO:0000269|PubMed:25535696"
FT MUTAGEN 45
FT /note="T->A: Slight decrease in phosphatase activity."
FT /evidence="ECO:0000269|PubMed:25535696"
FT MUTAGEN 53
FT /note="C->A: Lack of nitrosylation. Does not affect
FT phosphatase activity."
FT /evidence="ECO:0000269|PubMed:20830431"
FT MUTAGEN 67
FT /note="Y->A: Mutant can be phosphorylated."
FT /evidence="ECO:0000269|PubMed:19366344"
FT MUTAGEN 69
FT /note="T->A: No change in phosphatase activity."
FT /evidence="ECO:0000269|PubMed:25535696"
FT MUTAGEN 78
FT /note="T->A: No change in phosphatase activity."
FT /evidence="ECO:0000269|PubMed:25535696"
FT MUTAGEN 119
FT /note="T->A: No change in phosphatase activity."
FT /evidence="ECO:0000269|PubMed:25535696"
FT MUTAGEN 126
FT /note="D->A: Loss of phosphatase activity. Inhibits its
FT dephosphorylation activity on human VPS33B. Reduces its
FT effect on phagolysosome fusion in infected macrophages.
FT Still binds V-ATPase subunit H. 380-fold decrease in
FT catalytic efficiency toward pNPP at pH 7.0."
FT /evidence="ECO:0000269|PubMed:17975835,
FT ECO:0000269|PubMed:18474358, ECO:0000269|PubMed:22087003"
FT MUTAGEN 126
FT /note="D->N: 11-fold decrease in catalytic efficiency
FT toward pNPP at pH 7.0."
FT /evidence="ECO:0000269|PubMed:17975835"
FT MUTAGEN 128
FT /note="Y->A: Mutant can be phosphorylated. Lack of
FT phosphorylation and loss of phosphatase activity; when
FT associated with A-129."
FT /evidence="ECO:0000269|PubMed:19366344,
FT ECO:0000269|PubMed:25535696"
FT MUTAGEN 128
FT /note="Y->E: Loss of phosphatase activity; when associated
FT with E-129."
FT /evidence="ECO:0000269|PubMed:25535696"
FT MUTAGEN 129
FT /note="Y->A: Mutant can be phosphorylated. Lack of
FT phosphorylation and loss of phosphatase activity; when
FT associated with A-128."
FT /evidence="ECO:0000269|PubMed:19366344,
FT ECO:0000269|PubMed:25535696"
FT MUTAGEN 129
FT /note="Y->E: Loss of phosphatase activity; when associated
FT with E-128."
FT /evidence="ECO:0000269|PubMed:25535696"
FT MUTAGEN 140
FT /note="A->E: No longer binds to ubiquitin. Abolishes the
FT Jnk- and p38-dependent production of TNF and IL-1-beta in
FT macrophages. Also abolishes the PtpA-mediated inhibition of
FT phagosome acidification."
FT /evidence="ECO:0000269|PubMed:25642820"
FT MUTAGEN 146
FT /note="L->A: Retains phosphatase activity but does not bind
FT V-ATPase subunit H. Fails to inhibit V-ATPase trafficking
FT to phagosomes and shows impaired intracellular survival."
FT /evidence="ECO:0000269|PubMed:22087003"
FT STRAND 5..16
FT /evidence="ECO:0007829|PDB:1U2P"
FT HELIX 17..31
FT /evidence="ECO:0007829|PDB:1U2P"
FT TURN 35..37
FT /evidence="ECO:0007829|PDB:1U2P"
FT STRAND 38..46
FT /evidence="ECO:0007829|PDB:1U2P"
FT TURN 48..51
FT /evidence="ECO:0007829|PDB:1U2P"
FT HELIX 56..64
FT /evidence="ECO:0007829|PDB:1U2P"
FT HELIX 78..81
FT /evidence="ECO:0007829|PDB:1U2P"
FT STRAND 83..90
FT /evidence="ECO:0007829|PDB:1U2P"
FT HELIX 91..99
FT /evidence="ECO:0007829|PDB:1U2P"
FT HELIX 104..106
FT /evidence="ECO:0007829|PDB:1U2P"
FT STRAND 107..109
FT /evidence="ECO:0007829|PDB:1U2P"
FT HELIX 110..113
FT /evidence="ECO:0007829|PDB:1U2P"
FT HELIX 132..158
FT /evidence="ECO:0007829|PDB:1U2P"
SQ SEQUENCE 163 AA; 17892 MW; 9D1CF0DB24CA8E27 CRC64;
MSDPLHVTFV CTGNICRSPM AEKMFAQQLR HRGLGDAVRV TSAGTGNWHV GSCADERAAG
VLRAHGYPTD HRAAQVGTEH LAADLLVALD RNHARLLRQL GVEAARVRML RSFDPRSGTH
ALDVEDPYYG DHSDFEEVFA VIESALPGLH DWVDERLARN GPS
