MTRA_MYCTU
ID MTRA_MYCTU Reviewed; 228 AA.
AC P9WGM7; L0TES0; P0A5Z4; Q50447;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 41.
DE RecName: Full=DNA-binding response regulator MtrA;
GN Name=mtrA; OrderedLocusNames=Rv3246c; ORFNames=MTCY20B11.21c;
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 [GENOMIC DNA], CHARACTERIZATION, AND INDUCTION.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=8655513; DOI=10.1128/jb.178.11.3314-3321.1996;
RA Via L.E., Curcic R., Mudd M.H., Dhandayuthapani S., Ulmer R.J., Deretic V.;
RT "Elements of signal transduction in Mycobacterium tuberculosis: in vitro
RT phosphorylation and in vivo expression of the response regulator MtrA.";
RL J. Bacteriol. 178:3314-3321(1996).
RN [2]
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 [3]
RP INDUCTION, AND DISRUPTION PHENOTYPE.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=10851001; DOI=10.1128/jb.182.13.3832-3838.2000;
RA Zahrt T.C., Deretic V.;
RT "An essential two-component signal transduction system in Mycobacterium
RT tuberculosis.";
RL J. Bacteriol. 182:3832-3838(2000).
RN [4]
RP SUBCELLULAR LOCATION, INDUCTION, DNA-BINDING, PHOSPHORYLATION AT ASP-56,
RP AND MUTAGENESIS OF ASP-56.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=16629667; DOI=10.1111/j.1365-2958.2006.05137.x;
RA Fol M., Chauhan A., Nair N.K., Maloney E., Moomey M., Jagannath C.,
RA Madiraju M.V., Rajagopalan M.;
RT "Modulation of Mycobacterium tuberculosis proliferation by MtrA, an
RT essential two-component response regulator.";
RL Mol. Microbiol. 60:643-657(2006).
RN [5]
RP DNA-BINDING, AND COFACTOR.
RX PubMed=20671191; DOI=10.1093/jb/mvq082;
RA Li Y., Zeng J., He Z.G.;
RT "Characterization of a functional C-terminus of the Mycobacterium
RT tuberculosis MtrA responsible for both DNA binding and interaction with its
RT two-component partner protein, MtrB.";
RL J. Biochem. 148:549-556(2010).
RN [6]
RP FUNCTION, DNA-BINDING, PHOSPHORYLATION AT ASP-56, AND MUTAGENESIS OF
RP ASP-56.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=20223818; DOI=10.1074/jbc.m109.040097;
RA Rajagopalan M., Dziedzic R., Al Zayer M., Stankowska D., Ouimet M.C.,
RA Bastedo D.P., Marczynski G.T., Madiraju M.V.;
RT "Mycobacterium tuberculosis origin of replication and the promoter for
RT immunodominant secreted antigen 85B are the targets of MtrA, the essential
RT response regulator.";
RL J. Biol. Chem. 285:15816-15827(2010).
RN [7]
RP PROTEASOME SUBSTRATE, PUPYLATION AT LYS-207, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=20066036; DOI=10.1371/journal.pone.0008589;
RA Festa R.A., McAllister F., Pearce M.J., Mintseris J., Burns K.E.,
RA Gygi S.P., Darwin K.H.;
RT "Prokaryotic ubiquitin-like protein (Pup) proteome of Mycobacterium
RT tuberculosis.";
RL PLoS ONE 5:E8589-E8589(2010).
RN [8]
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 [9]
RP FUNCTION, SUBUNIT, INTERACTION WITH MTRB, DNA-BINDING, AND MUTAGENESIS OF
RP ASP-13 AND ASP-56.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21295603; DOI=10.1016/j.plasmid.2011.01.002;
RA Al Zayer M., Stankowska D., Dziedzic R., Sarva K., Madiraju M.V.,
RA Rajagopalan M.;
RT "Mycobacterium tuberculosis mtrA merodiploid strains with point mutations
RT in the signal-receiving domain of MtrA exhibit growth defects in nutrient
RT broth.";
RL Plasmid 65:210-218(2011).
RN [10]
RP FUNCTION, DNA-BINDING, AND MUTAGENESIS OF TYR-102.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=22610443; DOI=10.1074/jbc.m112.346544;
RA Plocinska R., Purushotham G., Sarva K., Vadrevu I.S., Pandeeti E.V.,
RA Arora N., Plocinski P., Madiraju M.V., Rajagopalan M.;
RT "Septal localization of the Mycobacterium tuberculosis MtrB sensor kinase
RT promotes MtrA regulon expression.";
RL J. Biol. Chem. 287:23887-23899(2012).
RN [11]
RP SUBUNIT.
RC STRAIN=H37Rv;
RX PubMed=32634279; DOI=10.1111/mmi.14571;
RA Zaveri A., Wang R., Botella L., Sharma R., Zhu L., Wallach J.B., Song N.,
RA Jansen R.S., Rhee K.Y., Ehrt S., Schnappinger D.;
RT "Depletion of the DarG antitoxin in Mycobacterium tuberculosis triggers the
RT DNA-damage response and leads to cell death.";
RL Mol. Microbiol. 114:641-652(2020).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) IN THE INACTIVE STATE, COFACTOR, AND
RP PHOSPHORYLATION.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=17511470; DOI=10.1021/bi602546q;
RA Friedland N., Mack T.R., Yu M., Hung L.W., Terwilliger T.C., Waldo G.S.,
RA Stock A.M.;
RT "Domain orientation in the inactive response regulator Mycobacterium
RT tuberculosis MtrA provides a barrier to activation.";
RL Biochemistry 46:6733-6743(2007).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-125, COFACTOR, AND SUBUNIT.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=20702407; DOI=10.1074/jbc.m110.157164;
RA Barbieri C.M., Mack T.R., Robinson V.L., Miller M.T., Stock A.M.;
RT "Regulation of response regulator autophosphorylation through interdomain
RT contacts.";
RL J. Biol. Chem. 285:32325-32335(2010).
CC -!- FUNCTION: Member of the two-component regulatory system MtrA/MtrB.
CC Binds direct repeat motifs of sequence 5'-GTCACAGCG-3', phosphorylation
CC confers higher affinity. Overexpression decreases bacteria viability
CC upon infection of human THP-1 macrophage cell line, due at least in
CC part to impaired blockage of phagosome-lysosome fusion (upon infection
CC bacteria usually remain in phagosomes). Infecting C57BL/6 mice with an
CC overexpressing strain leads to an attentuated infection in both spleen
CC and lungs. The level of dnaA mRNA increases dramatically. Binds the
CC promoter of dnaA, fbpD, ripA and itself, as well as oriC, which it may
CC regulate. Upon co-overexpression of MrtA and MtrB growth in macrophages
CC is partially restored, dnaA expression is not induced, although mouse
CC infections are still attenuated, suggesting that bacterial growth in
CC macrophages requires an optimal ratio of MtrB to MtrA.
CC {ECO:0000269|PubMed:20223818, ECO:0000269|PubMed:21295603,
CC ECO:0000269|PubMed:22610443}.
CC -!- COFACTOR:
CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108;
CC Evidence={ECO:0000269|PubMed:17511470, ECO:0000269|PubMed:20671191,
CC ECO:0000269|PubMed:20702407};
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:17511470, ECO:0000269|PubMed:20671191,
CC ECO:0000269|PubMed:20702407};
CC Note=Divalent cation. Ca(2+) and Mg(2+) have both been seen in crystal
CC structures. Optimal DNA-binding requires Ca(2+).
CC {ECO:0000269|PubMed:17511470, ECO:0000269|PubMed:20671191,
CC ECO:0000269|PubMed:20702407};
CC -!- SUBUNIT: Probably a monomer when inactive, phosphorylation may permit
CC it to oligomerize. It can oligomerize, and interacts with MrtB
CC (PubMed:20702407, PubMed:21295603). Co-immunoprecipitates with DarG in
CC the presence and absence of darT (PubMed:32634279).
CC {ECO:0000269|PubMed:20702407, ECO:0000269|PubMed:21295603,
CC ECO:0000269|PubMed:32634279}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000305|PubMed:16629667}.
CC -!- INDUCTION: Expressed in culture (at protein level). Constitutively
CC expressed in infected human blood-derived macrophages and mouse
CC macrophage cell line J774A. Autoregulates its own expression.
CC {ECO:0000269|PubMed:10851001, ECO:0000269|PubMed:16629667,
CC ECO:0000269|PubMed:8655513}.
CC -!- DOMAIN: C-terminal domain binds DNA and interacts with MtrB.
CC -!- PTM: Phosphorylated by MtrB (Probable). Autophosphorylates very slowly.
CC Phosphorylated protein binds DNA better than unphosphorylated.
CC {ECO:0000269|PubMed:16629667, ECO:0000269|PubMed:17511470,
CC ECO:0000269|PubMed:20223818, ECO:0000305}.
CC -!- PTM: Pupylated at Lys-207 by the prokaryotic ubiquitin-like protein
CC Pup, which leads to its degradation by the proteasome.
CC {ECO:0000269|PubMed:20066036}.
CC -!- DISRUPTION PHENOTYPE: Essential, it cannot be disrupted.
CC {ECO:0000269|PubMed:10851001}.
CC -!- MISCELLANEOUS: Was identified as a natural substrate of the
CC M.tuberculosis proteasome.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB07804.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; U01971; AAB07804.1; ALT_INIT; Genomic_DNA.
DR EMBL; AL123456; CCP46065.1; -; Genomic_DNA.
DR PIR; H70592; H70592.
DR RefSeq; NP_217763.1; NC_000962.3.
DR RefSeq; WP_003899985.1; NZ_NVQJ01000003.1.
DR PDB; 2GWR; X-ray; 2.10 A; A=1-228.
DR PDB; 3NHZ; X-ray; 2.50 A; A/B/C/D=1-125.
DR PDBsum; 2GWR; -.
DR PDBsum; 3NHZ; -.
DR AlphaFoldDB; P9WGM7; -.
DR SMR; P9WGM7; -.
DR STRING; 83332.Rv3246c; -.
DR PaxDb; P9WGM7; -.
DR DNASU; 888743; -.
DR GeneID; 45427240; -.
DR GeneID; 888743; -.
DR KEGG; mtu:Rv3246c; -.
DR TubercuList; Rv3246c; -.
DR eggNOG; COG0745; Bacteria.
DR PhylomeDB; P9WGM7; -.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR GO; GO:0032993; C:protein-DNA complex; IBA:GO_Central.
DR GO; GO:0001216; F:DNA-binding transcription activator activity; IBA:GO_Central.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0000156; F:phosphorelay response regulator activity; IBA:GO_Central.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IBA:GO_Central.
DR GO; GO:0051701; P:biological process involved in interaction with host; IMP:MTBBASE.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:MTBBASE.
DR GO; GO:0006468; P:protein phosphorylation; IDA:MTBBASE.
DR CDD; cd00383; trans_reg_C; 1.
DR Gene3D; 1.10.10.10; -; 1.
DR InterPro; IPR011006; CheY-like_superfamily.
DR InterPro; IPR001867; OmpR/PhoB-type_DNA-bd.
DR InterPro; IPR001789; Sig_transdc_resp-reg_receiver.
DR InterPro; IPR039420; WalR-like.
DR InterPro; IPR036388; WH-like_DNA-bd_sf.
DR PANTHER; PTHR48111; PTHR48111; 1.
DR Pfam; PF00072; Response_reg; 1.
DR Pfam; PF00486; Trans_reg_C; 1.
DR SMART; SM00448; REC; 1.
DR SMART; SM00862; Trans_reg_C; 1.
DR SUPFAM; SSF52172; SSF52172; 1.
DR PROSITE; PS51755; OMPR_PHOB; 1.
DR PROSITE; PS50110; RESPONSE_REGULATORY; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytoplasm; DNA-binding; Isopeptide bond; Metal-binding;
KW Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation; Two-component regulatory system; Ubl conjugation.
FT CHAIN 1..228
FT /note="DNA-binding response regulator MtrA"
FT /id="PRO_0000081143"
FT DOMAIN 7..120
FT /note="Response regulatory"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00169"
FT DNA_BIND 128..227
FT /note="OmpR/PhoB-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01091"
FT BINDING 13
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT BINDING 56
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT BINDING 59
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT MOD_RES 56
FT /note="4-aspartylphosphate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00169,
FT ECO:0000269|PubMed:16629667, ECO:0000269|PubMed:20223818"
FT CROSSLNK 207
FT /note="Isoglutamyl lysine isopeptide (Lys-Gln) (interchain
FT with Q-Cter in protein Pup)"
FT /evidence="ECO:0000269|PubMed:20066036"
FT MUTAGEN 13
FT /note="D->A: No phosphorylation by EnvZ kinase in vitro.
FT Binds fbpB and oriC DNA in the presence and absence of EnvZ
FT and ATP. A merodiploid strain has late growth defects, fbpB
FT is down-regulated. May be constitutively active."
FT /evidence="ECO:0000269|PubMed:21295603"
FT MUTAGEN 56
FT /note="D->E: No phosphorylation by EnvZ kinase in vitro.
FT Binds DNA in the absence but not presence of EnvZ and ATP.
FT A merodiploid strain has late growth defects. May mimic the
FT phosphorylated state."
FT /evidence="ECO:0000269|PubMed:16629667,
FT ECO:0000269|PubMed:20223818, ECO:0000269|PubMed:21295603"
FT MUTAGEN 56
FT /note="D->N: No phosphorylation by EnvZ kinase in vitro,
FT does not bind DNA. Poor growth in infected macrophages and
FT upon mouse infection. Fewer bacteria are mistargeted to
FT lysosomes."
FT /evidence="ECO:0000269|PubMed:16629667,
FT ECO:0000269|PubMed:20223818, ECO:0000269|PubMed:21295603"
FT MUTAGEN 102
FT /note="Y->C: Phosphorylated by EnvZ kinase in vitro,
FT reverses many phenotypes of mtrB knockout."
FT /evidence="ECO:0000269|PubMed:22610443"
FT STRAND 7..11
FT /evidence="ECO:0007829|PDB:2GWR"
FT HELIX 15..27
FT /evidence="ECO:0007829|PDB:2GWR"
FT STRAND 31..35
FT /evidence="ECO:0007829|PDB:2GWR"
FT HELIX 38..40
FT /evidence="ECO:0007829|PDB:2GWR"
FT HELIX 41..48
FT /evidence="ECO:0007829|PDB:2GWR"
FT STRAND 51..58
FT /evidence="ECO:0007829|PDB:2GWR"
FT STRAND 60..62
FT /evidence="ECO:0007829|PDB:2GWR"
FT HELIX 64..72
FT /evidence="ECO:0007829|PDB:2GWR"
FT STRAND 79..84
FT /evidence="ECO:0007829|PDB:2GWR"
FT HELIX 91..96
FT /evidence="ECO:0007829|PDB:2GWR"
FT STRAND 101..106
FT /evidence="ECO:0007829|PDB:2GWR"
FT HELIX 109..119
FT /evidence="ECO:0007829|PDB:2GWR"
FT STRAND 130..133
FT /evidence="ECO:0007829|PDB:2GWR"
FT STRAND 136..139
FT /evidence="ECO:0007829|PDB:2GWR"
FT TURN 140..143
FT /evidence="ECO:0007829|PDB:2GWR"
FT STRAND 144..147
FT /evidence="ECO:0007829|PDB:2GWR"
FT STRAND 150..152
FT /evidence="ECO:0007829|PDB:2GWR"
FT HELIX 156..167
FT /evidence="ECO:0007829|PDB:2GWR"
FT HELIX 175..181
FT /evidence="ECO:0007829|PDB:2GWR"
FT HELIX 192..205
FT /evidence="ECO:0007829|PDB:2GWR"
FT STRAND 213..218
FT /evidence="ECO:0007829|PDB:2GWR"
FT TURN 219..221
FT /evidence="ECO:0007829|PDB:2GWR"
FT STRAND 222..225
FT /evidence="ECO:0007829|PDB:2GWR"
SQ SEQUENCE 228 AA; 25279 MW; 925DEBC495DFD5B6 CRC64;
MDTMRQRILV VDDDASLAEM LTIVLRGEGF DTAVIGDGTQ ALTAVRELRP DLVLLDLMLP
GMNGIDVCRV LRADSGVPIV MLTAKTDTVD VVLGLESGAD DYIMKPFKPK ELVARVRARL
RRNDDEPAEM LSIADVEIDV PAHKVTRNGE QISLTPLEFD LLVALARKPR QVFTRDVLLE
QVWGYRHPAD TRLVNVHVQR LRAKVEKDPE NPTVVLTVRG VGYKAGPP
