Rv3246c (mtrA)

Current annotations:
- TBCAP: (community-based annotations - see table at bottom of page)
- TBDB: DNA-binding response regulator mtrA
- REFSEQ: two component sensory transduction transcriptional regulatory protein MTRA
- PATRIC: DNA-binding response regulator mtrA
- TUBERCULIST: Two component sensory transduction transcriptional regulatory protein MtrA
- NCBI: Two component sensory transduction transcriptional regulatory protein MtrA
- updated information (H37Rv4):
  - gene name: mtrA
  - function:
  - reference:
Type: Not Target
Start: 3626663
End: 3627349
Operon:

Trans-membrane region:
Role: I.J.2 - Two component systems
GO terms:
- GO:0046872 - metal ion binding (Uniprot)
- GO:0045893 - positive regulation of transcription, DNA-templated (Uniprot)
- GO:0044117 - growth of symbiont in host (Uniprot)
- GO:0006468 - protein phosphorylation (Uniprot)
- GO:0006355 - regulation of transcription, DNA-templated (Uniprot)
- GO:0006351 - transcription, DNA-templated (Uniprot)
- GO:0005886 - plasma membrane (Uniprot)
- GO:0005737 - cytoplasm (Uniprot)
- GO:0003677 - DNA binding (Uniprot)
- GO:0000160 - phosphorelay signal transduction system (Uniprot)
Reaction(s) (based on iSM810 metabolic model):
Gene Expression Profile (Transcriptional Responses to Drugs; Boshoff et al, 2004)
Gene Modules extracted from cluster analysis of 249 transcriptomic datasets using ICA
Orthologs among selected mycobacteria
Protein structure: 2gwr, 3nhz
Search for Homologs in PDB

Top 10 Homologs in PDB (as of Nov 2020):

PDB	aa ident	species	PDB title
3NHZ	100%	Mycobacterium tuberculosis	Structure of N-terminal Domain of MtrA
2GWR	100%	Mycobacterium tuberculosis	Crystal structure of the response regulator protein mtrA from Mycobacterium Tuberculosis
3F6P	52%	Bacillus subtilis	Crystal Structure of unphosphorelated receiver domain of YycF
2ZWM	52%	Bacillus subtilis	Crystal structure of YycF receiver domain from Bacillus subtilis
4UHS	51%	ESCHERICHIA COLI	Crystal structure of the receiver domain of CpxR from E. coli (tetragonal form)
4UHK	51%	ESCHERICHIA COLI	Crystal structure of the receiver domain of CpxR from E. coli (phosphorylated)
4UHJ	51%	ESCHERICHIA COLI	Crystal structure of the receiver domain of CpxR from E. coli (orthorhombic form)
2IYN	50%	ESCHERICHIA COLI	The co-factor-induced pre-active conformation in PhoB
1ZES	50%	Escherichia coli	BeF3- activated PhoB receiver domain
1B00	50%	Escherichia coli	PHOB RECEIVER DOMAIN FROM ESCHERICHIA COLI

Links to additional information on mtrA:
- TBDB (updated)
- Phyre2 structure prediction, model: final.casp.pdb (from Mao et al, 2013)
- UniProt
- AlphaFold model
- Vulnerability = -5.325 (from Jeremy Rock's lab)
- KEGG - nucleotide and amino acid sequences of gene
- Mycobrowser
- PATRIC
- BioCyc
- Systems Biology

Amino Acid Sequence

MDTMRQRILVVDDDASLAEMLTIVLRGEGFDTAVIGDGTQALTAVRELRPDLVLLDLMLPGMNGIDVCRVLRADSGVPIVMLTAKTDTVDVVLGLESGAD
DYIMKPFKPKELVARVRARLRRNDDEPAEMLSIADVEIDVPAHKVTRNGEQISLTPLEFDLLVALARKPRQVFTRDVLLEQVWGYRHPADTRLVNVHVQR
LRAKVEKDPENPTVVLTVRGVGYKAGPP

(Nucleotide sequence available on KEGG)

Additional Information

Analysis of Positive Selection in Clinical Isolates new

Analysis of dN/dS (omega) in two collections of Mtb clinical isolates using GenomegaMap (Window model) (see description of methods)
- Moldova: 2,057 clinical isolates
- global set: 5,195 clinical isolates from 15 other countries
In the omega plots, the black line shows the mean estimate of omega (dN/dS) at each codon, and the blue lines are the bounds for the 95% credible interval (95%CI, from MCMC sampling).
A gene is under significant positive selection if the lower-bound of the 95%CI of omega (lower blue line) exceeds 1.0 at any codon.

	Moldova (2,057)	global set (5,195)
under significant positive selection?	NO	NO
omega peak height (95%CI lower bound)	0.63 (0.01)	1.07 (0.21)
codons under selection
omega plots
genetic variants*	link	link
statistics at each codon	link	link

* example format for variants: "D27 (GAC): D27H (CAC,11)" means "Asp27 (native codon GAC) mutated to His (codon CAC) in 11 isolates"

ESSENTIALITY

MtbTnDB - interactive tool for exploring a database of published TnSeq datasets for Mtb

TnSeqCorr - genes with correlated TnSeq profiles across ~100 conditions

Rv3246c/mtrA, gene len: 686 bp, num TA sites: 11

condition	dataset	call	medium	method	notes
in-vitro	DeJesus 2017 mBio	essential	7H9	HMM	fully saturated, 14 TnSeq libraries combined
in-vitro	Sassetti 2003 Mol Micro	no data	7H9	TRASH	essential if hybridization ratio<0.2
in-vivo (mice)	Sassetti 2003 PNAS	essential	BL6 mice	TRASH	essential if hybridization ratio<0.4, min over 4 timepoints (1-8 weeks)
in-vitro (glycerol)	Griffin 2011 PPath	essential	M9 minimal+glycerol	Gumbel	2 replicates; Padj<0.05
in-vitro (cholesterol)	Griffin 2011 PPath	essential	M9 minimal+cholesterol	Gumbel	3 replicates; Padj<0.05
differentially essential in cholesterol	Griffin 2011 PPath	NO (LFC=0.0)	cholesterol vs glycerol	resampling-SR	YES if Padj<0.05, else not significant; LFC<0 means less insertions/more essential in cholesterol
in-vitro	Smith 2022 eLife	essential	7H9	HMM	6 replicates (raw data in Subramaniam 2017, PMID 31752678)
in-vivo (mice)	Smith 2022 eLife	essential	BL6 mice	HMM	6 replicates (raw data in Subramaniam 2017, PMID 31752678)
differentially essential in mice	Smith 2022 eLife	NO (LFC=0.0)	in-vivo vs in-vitro	ZINB	YES if Padj<0.05, else not significant; LFC<0 means less insertions/more essential in mice
in-vitro (minimal)	Minato 2019 mSys	growth defect	minimal medium	HMM
in-vitro (YM rich medium)	Minato 2019 mSys	essential	YM rich medium	HMM	7H9 supplemented with ~20 metabolites (amino acids, vitamins)
differentially essential in YM rich medium	Minato 2019 mSys	NO (LFC=0.0)	YM rich vs minimal medium	resampling

TnSeq Data No data currently available.

No TnSeq data currently available for this Target.

RNASeq Data No data currently available.

No RNA-Seq data currently available for this Target.

Metabolomic Profiles No data currently available.

No Metabolomic data currently available for this Target.

Proteomic Data No data currently available.

No Proteomic data currently available for this Target.

Regulatory Relationships from Systems Biology

BioCyc

Gene interactions based on ChIPSeq and Transcription Factor Over-Expression (TFOE) (Systems Biology)

NOTE: Green edges represent the connected genes being classified as differentially essential as a result of the middle gene being knocked out. These interactions are inferred based on RNASeq.

Interactions based on ChIPSeq data

Binds To:
Bound By:

Interactions based on ChIPSeq data (Minch et al. 2014)

Binds To:
- Rv0040c (mtc28) (Direct binding)
- Rv0041 (leuS) (Direct binding)
- Rv0113 (gmhA) (Direct binding)
- Rv0116c (ldtA) (Direct binding)
- Rv0129c (fbpC) (Direct binding)
- Rv0130 (htdZ) (Direct binding)
- Rv0179c (lprO) (Direct binding)
- Rv0188 (-) (Direct binding)
- Rv0208c (-) (Direct binding)
- Rv0209 (-) (Direct binding)
- Rv0252 (nirB) (Direct binding)
- Rv0309 (-) (Direct binding)
- Rv0320 (-) (Direct binding)
- Rv0456A (mazF1) (Direct binding)
- Rv0469 (umaA) (Direct binding)
- Rv0643c (mmaA3) (Direct binding)
- Rv0653c (-) (Direct binding)
- Rv0654 (-) (Direct binding)
- Rv0822c (-) (Direct binding)
- Rv0950c (-) (Direct binding)
- Rv0996 (-) (Direct binding)
- Rv1004c (-) (Direct binding)
- Rv1009 (rpfB) (Direct binding)
- Rv1089A (celA2a) (Direct binding)
- Rv1116 (-) (Direct binding)
- Rv1158c (-) (Direct binding)
- Rv1159 (pimE) (Direct binding)
- Rv1169c (lipX) (Direct binding)
- Rv1170 (mshB) (Direct binding)
- Rv1268c (-) (Direct binding)
- Rv1433 (-) (Direct binding)
- Rv1469 (ctpD) (Direct binding)
- Rv1477 (ripA) (Direct binding)
- Rv1522c (mmpL12) (Direct binding)
- Rv1523 (-) (Direct binding)
- Rv1690 (lprJ) (Direct binding)
- Rv1754c (-) (Direct binding)
- Rv1772 (-) (Direct binding)
- Rv1791 (PE19) (Direct binding)
- Rv1815 (-) (Direct binding)
- Rv1883c (-) (Direct binding)
- Rv1884c (rpfC) (Direct binding)
- Rv1886c (fbpB) (Direct binding)
- Rv1908c (katG) (Direct binding)
- Rv1918c (PPE35) (Direct binding)
- Rv1987 (-) (Direct binding)
- Rv2162c (PE_PGRS38) (Direct binding)
- Rv2243 (fabD) (Direct binding)
- Rv2293c (-) (Direct binding)
- Rv2352c (PPE38) (Direct binding)
- Rv2462c (tig) (Direct binding)
- Rv2463 (lipP) (Direct binding)
- Rv2525c (-) (Direct binding)
- Rv2722 (-) (Direct binding)
- Rv2723 (-) (Direct binding)
- Rv2758c (vapB21) (Direct binding)
- Rv2864c (-) (Direct binding)
- Rv2884 (-) (Direct binding)
- Rv3159c (PPE53) (Direct binding)
- Rv3171c (hpx) (Direct binding)
- Rv3241c (-) (Direct binding)
- Rv3245c (mtrB) (Direct binding)
- Rv3246c (mtrA) (Direct binding)
- Rv3276c (purK) (Direct binding)
- Rv3277 (-) (Direct binding)
- Rv3354 (-) (Direct binding)
- Rv3532 (PPE61) (Direct binding)
- Rv3583c (-) (Direct binding)
- Rv3645 (-) (Direct binding)
- Rv3674c (nth) (Direct binding)
- Rv3675 (-) (Direct binding)
- Rv3676 (crp) (Direct binding)
- Rv3681c (whiB4) (Direct binding)
- Rv3716c (-) (Direct binding)
- Rv3717 (-) (Direct binding)
- Rv3810 (pirG) (Direct binding)
- Rv0114 (gmhB) (Upstream of operon)
- Rv0115 (hddA) (Upstream of operon)
- Rv0207c (-) (Upstream of operon)
- Rv0210 (-) (Upstream of operon)
- Rv0253 (nirD) (Upstream of operon)
- Rv0321 (dcd) (Upstream of operon)
- Rv0655 (mkl) (Upstream of operon)
- Rv1010 (ksgA) (Upstream of operon)
- Rv1090 (celA2b) (Upstream of operon)
- Rv1157c (-) (Upstream of operon)
- Rv1168c (PPE17) (Upstream of operon)
- Rv1434 (-) (Upstream of operon)
- Rv1478 (-) (Upstream of operon)
- Rv1524 (-) (Upstream of operon)
- Rv1691 (-) (Upstream of operon)
- Rv1692 (-) (Upstream of operon)
- Rv1693 (-) (Upstream of operon)
- Rv1694 (tlyA) (Upstream of operon)
- Rv1695 (ppnK) (Upstream of operon)
- Rv1696 (recN) (Upstream of operon)
- Rv1882c (-) (Upstream of operon)
- Rv1885c (-) (Upstream of operon)
- Rv2292c (-) (Upstream of operon)
- Rv3244c (lpqB) (Upstream of operon)
- Rv3274c (fadE25) (Upstream of operon)
- Rv3275c (purE) (Upstream of operon)
- Rv3581c (ispF) (Upstream of operon)
- Rv3582c (ispD) (Upstream of operon)
- Rv3673c (-) (Upstream of operon)
- Rv3715c (recR) (Upstream of operon)
Bound By:
- Rv1353c (-) (Direct binding)
- Rv2324 (-) (Direct binding)
- Rv3246c (mtrA) (Direct binding)
- Rv3830c (-) (Direct binding)

Interactions based on TFOE data (Rustad et al. 2014)

Upregulates:
- Does not upregulate other genes.
Upregulated by:
- Not upregulated by other genes.
Downregulates:
- Does not downregulate other genes.
Downregulated by:

Property	Value	Creator	Evidence	PMID	Comment
Citation	Mycobacterium tuberculosis ECF sigma factor sigC is required for lethality in mice and for the conditional expression of a defined gene set. R. Sun, PJ. Converse et al. Mol. Microbiol. 2004	sourish10	IEP	15049808	Co-expression (Functional linkage)
Interaction	Signaling Rv2069	sourish10	IEP		Co-expression (Functional linkage) R. Sun, PJ. Converse et al. Mycobacterium tuberculosis ECF sigma factor sigC is required for lethality in mice and for the conditional expression of a defined gene set. Mol. Microbiol. 2004
Interaction	Signaling Rv3245c	sourish10	IPI		Co-expression (Functional linkage) TC. Zahrt & V. Deretic An essential two-component signal transduction system in Mycobacterium tuberculosis. J. Bacteriol. 2000
Interaction	Signaling Rv3245c	sourish10	IPI		Co-expression (Functional linkage) KK. Singh, X. Zhang et al. Antigens of Mycobacterium tuberculosis expressed during preclinical tuberculosis: serological immunodominance of proteins with repetitive amino acid sequences. Infect. Immun. 2001
Citation	The two-component regulatory system mtrAB is required for morphotypic multidrug resistance in Mycobacterium avium. authors,GA. Cangelosi,JS. Do,R. Freeman,JG. Bennett,M. Semret,MA. Behr Antimicrob. Agents Chemother. 2006	sourish10	TAS	16436697	Co-expression (Functional linkage)
Interaction	Signaling Rv3245c	sourish10	TAS		Co-expression (Functional linkage) authors,GA. Cangelosi,JS. Do,R. Freeman,JG. Bennett,M. Semret,MA. Behr The two-component regulatory system mtrAB is required for morphotypic multidrug resistance in Mycobacterium avium. Antimicrob. Agents Chemother. 2006
Citation	An essential two-component signal transduction system in Mycobacterium tuberculosis. TC. Zahrt & V. Deretic J. Bacteriol. 2000	sourish10	TAS	10851001	Co-expression (Functional linkage)
Interaction	Signaling Rv3245c	sourish10	TAS		Co-expression (Functional linkage) TC. Zahrt & V. Deretic An essential two-component signal transduction system in Mycobacterium tuberculosis. J. Bacteriol. 2000
Citation	Antigens of Mycobacterium tuberculosis expressed during preclinical tuberculosis: serological immunodominance of proteins with repetitive amino acid sequences. KK. Singh, X. Zhang et al. Infect. Immun. 2001	sourish10	TAS	11349098	Co-expression (Functional linkage)
Interaction	Signaling Rv3245c	sourish10	TAS		Co-expression (Functional linkage) KK. Singh, X. Zhang et al. Antigens of Mycobacterium tuberculosis expressed during preclinical tuberculosis: serological immunodominance of proteins with repetitive amino acid sequences. Infect. Immun. 2001
Interaction	Regulatory Rv3244c	harsharohiratruefriend	IMP		Co-expression (Functional linkage) N. Mker, M. Brocker et al. Deletion of the genes encoding the MtrA-MtrB two-component system of Corynebacterium glutamicum has a strong influence on cell morphology, antibiotics susceptibility and expression of genes involved in osmoprotection. Mol. Microbiol. 2004
Interaction	Regulatory Rv3244c	harsharohiratruefriend	IMP		Co-expression (Functional linkage) authors,PA. Hoskisson,MI. Hutchings MtrAB-LpqB: a conserved three-component system in actinobacteria? Trends Microbiol. 2006
Interaction	Signaling Rv3245c	sourish10	IPI		Co-expression (Functional linkage) authors,GA. Cangelosi,JS. Do,R. Freeman,JG. Bennett,M. Semret,MA. Behr The two-component regulatory system mtrAB is required for morphotypic multidrug resistance in Mycobacterium avium. Antimicrob. Agents Chemother. 2006
Interaction	Regulatory Rv2069	priti.priety	IEP		Co-expression (Functional linkage) R. Sun, PJ. Converse et al. Mycobacterium tuberculosis ECF sigma factor sigC is required for lethality in mice and for the conditional expression of a defined gene set. Mol. Microbiol. 2004
Interaction	Regulatory Rv2069	ashwinigbhat	IEP		Co-expression (Functional linkage) R. Sun, PJ. Converse et al. Mycobacterium tuberculosis ECF sigma factor sigC is required for lethality in mice and for the conditional expression of a defined gene set. Mol. Microbiol. 2004

TB Genome Annotation Portal