PPE02_MYCTU
ID PPE02_MYCTU Reviewed; 556 AA.
AC P9WI47; L0T342; Q79FZ4; Q7DA58;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 25-MAY-2022, entry version 35.
DE RecName: Full=PPE family protein PPE2 {ECO:0000305};
GN Name=PPE2; OrderedLocusNames=Rv0256c;
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 IDENTIFICATION AS A DRUG TARGET [LARGE SCALE ANALYSIS].
RX PubMed=19099550; DOI=10.1186/1752-0509-2-109;
RA Raman K., Yeturu K., Chandra N.;
RT "targetTB: a target identification pipeline for Mycobacterium tuberculosis
RT through an interactome, reactome and genome-scale structural analysis.";
RL BMC Syst. Biol. 2:109-109(2008).
RN [3]
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 [4]
RP PRELIMINARY FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=23448669; DOI=10.1111/nyas.12070;
RA Bhat K.H., Das A., Srikantam A., Mukhopadhyay S.;
RT "PPE2 protein of Mycobacterium tuberculosis may inhibit nitric oxide in
RT activated macrophages.";
RL Ann. N. Y. Acad. Sci. 1283:97-101(2013).
RN [5]
RP FUNCTION AS A CANDIDATE FOR SERODIAGNOSIS.
RX PubMed=23827809; DOI=10.1016/j.meegid.2013.06.023;
RA Abraham P.R., Latha G.S., Valluri V.L., Mukhopadhyay S.;
RT "Mycobacterium tuberculosis PPE protein Rv0256c induces strong B cell
RT response in tuberculosis patients.";
RL Infect. Genet. Evol. 22:244-249(2014).
RN [6]
RP FUNCTION AS A CANDIDATE FOR SERODIAGNOSIS.
RX PubMed=26364913; DOI=10.1016/j.meegid.2015.09.005;
RA Abraham P.R., Udgata A., Latha G.S., Mukhopadhyay S.;
RT "The Mycobacterium tuberculosis PPE protein Rv1168c induces stronger B cell
RT response than Rv0256c in active TB patients.";
RL Infect. Genet. Evol. 40:339-345(2016).
RN [7]
RP FUNCTION, SUBCELLULAR LOCATION, AND DOMAIN.
RX PubMed=28071726; DOI=10.1038/srep39706;
RA Bhat K.H., Srivastava S., Kotturu S.K., Ghosh S., Mukhopadhyay S.;
RT "The PPE2 protein of Mycobacterium tuberculosis translocates to host
RT nucleus and inhibits nitric oxide production.";
RL Sci. Rep. 7:39706-39706(2017).
RN [8]
RP REVIEW.
RX PubMed=28481123; DOI=10.2217/fmb-2017-0038;
RA Mukhopadhyay S., Ghosh S.;
RT "Mycobacterium tuberculosis: what is the role of PPE2 during infection?";
RL Future Microbiol. 12:457-460(2017).
RN [9]
RP FUNCTION, DOMAIN, AND MUTAGENESIS OF TYR-209; TRP-236 AND PRO-249.
RX PubMed=31375544; DOI=10.4049/jimmunol.1801143;
RA Srivastava S., Battu M.B., Khan M.Z., Nandicoori V.K., Mukhopadhyay S.;
RT "Mycobacterium tuberculosis PPE2 protein interacts with p67phox and
RT inhibits reactive oxygen species production.";
RL J. Immunol. 203:1218-1229(2019).
CC -!- FUNCTION: Inhibits nitric oxide (NO) production in activated
CC macrophages (PubMed:23448669, PubMed:28071726). Acts by inhibiting
CC expression of the host inducible nitric oxide synthase (iNOS)
CC (PubMed:28071726). PPE2 is translocated into the host macrophage
CC nucleus, where it interacts with a GATA-binding site overlapping with
CC the TATA box of NOS2 (iNOS) promoter, and strongly inhibits NOS2 gene
CC transcription (PubMed:28071726). Reduction in NO production in turn
CC facilitates intracellular survival of the bacilli inside the macrophage
CC (PubMed:28071726). In addition, disrupts the assembly of NADPH oxidase
CC complex, which inhibits NADPH oxidase-mediated reactive oxygen species
CC (ROS) generation in macrophages and favors M.tuberculosis survival
CC (PubMed:31375544). Acts by interacting with NCF2, the cytosolic subunit
CC of NADPH oxidase, and preventing translocation of NCF2 and NCF1 to the
CC membrane, which causes a reduction of the functional assembly of NADPH
CC oxidase complex and a decrease in NADPH oxidase activity
CC (PubMed:31375544). {ECO:0000269|PubMed:23448669,
CC ECO:0000269|PubMed:28071726, ECO:0000269|PubMed:31375544}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:23448669}. Host
CC cytoplasm {ECO:0000269|PubMed:28071726, ECO:0000305|PubMed:23448669}.
CC Host nucleus {ECO:0000269|PubMed:28071726}. Note=Translocated into the
CC macrophage nucleus via the classical importin alpha/beta pathway.
CC {ECO:0000269|PubMed:28071726}.
CC -!- DOMAIN: Contains a conserved PPE N-terminal domain and a variable C-
CC terminal domain (PubMed:31375544). The C-terminal region includes a
CC SH3-like region, a leucine zipper DNA-binding motif and a functional
CC nuclear localization signal (NLS) (PubMed:28071726, PubMed:31375544).
CC {ECO:0000269|PubMed:28071726, ECO:0000269|PubMed:31375544}.
CC -!- MISCELLANEOUS: Shows a strong immunoreactivity toward tuberculosis
CC patient sera compared to that of BCG-vaccinated controls. Could be an
CC attractive candidate for serodiagnosis to discriminate patients with
CC active tuberculosis from BCG-vaccinated individuals (PubMed:23827809,
CC PubMed:26364913). Could diagnose both pulmonary and extrapulmonary
CC tuberculosis cases (PubMed:23827809). However, it has lower sensitivity
CC to detect smear negative and extrapulmonary cases as compared to
CC PPE17/Rv1168c (PubMed:26364913). {ECO:0000269|PubMed:23827809,
CC ECO:0000269|PubMed:26364913}.
CC -!- MISCELLANEOUS: Was identified as a high-confidence drug target.
CC {ECO:0000269|PubMed:19099550}.
CC -!- SIMILARITY: Belongs to the mycobacterial PPE family. {ECO:0000305}.
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DR EMBL; AL123456; CCP42985.1; -; Genomic_DNA.
DR PIR; D70940; D70940.
DR RefSeq; WP_003401347.1; NZ_KK339370.1.
DR RefSeq; YP_177704.1; NC_000962.3.
DR AlphaFoldDB; P9WI47; -.
DR SMR; P9WI47; -.
DR STRING; 83332.Rv0256c; -.
DR PaxDb; P9WI47; -.
DR DNASU; 886684; -.
DR GeneID; 886684; -.
DR KEGG; mtu:Rv0256c; -.
DR PATRIC; fig|83332.111.peg.289; -.
DR TubercuList; Rv0256c; -.
DR eggNOG; COG5651; Bacteria.
DR OMA; YPMDIGT; -.
DR Reactome; R-HSA-9636249; Inhibition of nitric oxide production.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0030430; C:host cell cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0042025; C:host cell nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR Gene3D; 1.20.1260.20; -; 1.
DR InterPro; IPR043641; PPE-PPW_C.
DR InterPro; IPR000030; PPE_family.
DR InterPro; IPR038332; PPE_sf.
DR Pfam; PF00823; PPE; 1.
DR Pfam; PF18878; PPE-PPW; 1.
PE 1: Evidence at protein level;
KW Host cytoplasm; Host nucleus; Reference proteome; Secreted; Virulence.
FT CHAIN 1..556
FT /note="PPE family protein PPE2"
FT /id="PRO_0000378473"
FT REGION 8..164
FT /note="PPE"
FT /evidence="ECO:0000305"
FT REGION 201..256
FT /note="SH3-like"
FT /evidence="ECO:0000305|PubMed:31375544"
FT REGION 319..340
FT /note="Leucine zipper motif"
FT /evidence="ECO:0000305|PubMed:28071726"
FT REGION 385..418
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 443..556
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 473..481
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000305|PubMed:28071726,
FT ECO:0000305|PubMed:31375544"
FT COMPBIAS 385..416
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MUTAGEN 209
FT /note="Y->A: Does not affect interaction with NCF2 and ROS
FT production."
FT /evidence="ECO:0000269|PubMed:31375544"
FT MUTAGEN 236
FT /note="W->A: Does not interact with NCF2 and cannot inhibit
FT ROS production."
FT /evidence="ECO:0000269|PubMed:31375544"
FT MUTAGEN 249
FT /note="P->A: Does not affect interaction with NCF2 and ROS
FT production."
FT /evidence="ECO:0000269|PubMed:31375544"
SQ SEQUENCE 556 AA; 56952 MW; 18F3D29548F9206D CRC64;
MTAPIWMASP PEVHSALLSS GPGPGPLLVS AEGWHSLSIA YAETADELAA LLAAVQAGTW
DGPTAAVYVA AHTPYLAWLV QASANSAAMA TRQETAATAY GTALAAMPTL AELGANHALH
GVLMATNFFG INTIPIALNE SDYARMWIQA ATTMASYQAV STAAVAAAPQ TTPAPQIVKA
NAPTAASDEP NQVQEWLQWL QKIGYTDFYN NVIQPFINWL TNLPFLQAMF SGFDPWLPSL
GNPLTFLSPA NIAFALGYPM DIGSYVAFLS QTFAFIGADL AAAFASGNPA TIAFTLMFTT
VEAIGTIITD TIALVKTLLE QTLALLPAAL PLLAAPLAPL TLAPASAAGG FAGLSGLAGL
VGIPPSAPPV IPPVAAIAPS IPTPTPTPAP APAPTAVTAP TPPPGPPPPP VTAPPPVTGA
GIQSFGYLVG DLNSAAQARK AVGTGVRKKT PEPDSAEAPA AAAAPEEQVQ PQRRRRPKIK
QLGRGYEYLD LDPETGHDPT GSPQGAGTLG FAGTTHKASP GQVAGLITLP NDAFGGSPRT
PMMPGTWDTD SATRVE
