Rv0596c (vapB4)

Current annotations:
- TBCAP: (community-based annotations - see table at bottom of page)
- TBDB: antitoxin
- REFSEQ: hypothetical protein
- PATRIC: FIG044579: hypothetical protein
- TUBERCULIST: Possible antitoxin VapB4
- NCBI: Possible antitoxin VapB4
- updated information (H37Rv4):
  - gene name: vapB4
  - function:
  - reference:
Type: Not Target
Start: 695228
End: 695485
Operon:

Trans-membrane region:
Role: V - Conserved hypotheticals
GO terms:
- GO:0097351 - toxin-antitoxin pair type II binding (Uniprot)
- GO:0045927 - positive regulation of growth (Uniprot)
- GO:0005515 - protein binding (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:
Search for Homologs in PDB
Top 10 Homologs in PDB (as of Nov 2020):

PDB aa ident species PDB title

3DBO 44% Mycobacterium tuberculosis Crystal structure of a member of the VapBC family of toxin-antitoxin systems, VapBC-5, from Mycobacterium tuberculosis
Links to additional information on vapB4:
- TBDB (updated)
- Phyre2 structure prediction, model: final.casp.pdb (from Mao et al, 2013)
- UniProt
- AlphaFold model
- Vulnerability = -0.152 (from Jeremy Rock's lab)
- KEGG - nucleotide and amino acid sequences of gene
- Mycobrowser
- PATRIC
- BioCyc
- Systems Biology

PDB	aa ident	species	PDB title
3DBO	44%	Mycobacterium tuberculosis	Crystal structure of a member of the VapBC family of toxin-antitoxin systems, VapBC-5, from Mycobacterium tuberculosis

Amino Acid Sequence

MSATIPARDLRNHTAEVLRRVAAGEEIEVLKDNRPVARIVPLKRRRQWLPAAEVIGELVRLGPDTTNLGEELRETLTQTTDDVRW

(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)	1.21 (0.17)	1.42 (0.4)
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

Rv0596c/vapB4, gene len: 257 bp, num TA sites: 5

condition	dataset	call	medium	method	notes
in-vitro	DeJesus 2017 mBio	non-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	no data	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	non-essential	M9 minimal+cholesterol	Gumbel	3 replicates; Padj<0.05
differentially essential in cholesterol	Griffin 2011 PPath	NO (LFC=2.81)	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	non-essential	7H9	HMM	6 replicates (raw data in Subramaniam 2017, PMID 31752678)
in-vivo (mice)	Smith 2022 eLife	non-essential	BL6 mice	HMM	6 replicates (raw data in Subramaniam 2017, PMID 31752678)
differentially essential in mice	Smith 2022 eLife	NO (LFC=-0.212)	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	non-essential	minimal medium	HMM
in-vitro (YM rich medium)	Minato 2019 mSys	non-essential	YM rich medium	HMM	7H9 supplemented with ~20 metabolites (amino acids, vitamins)
differentially essential in YM rich medium	Minato 2019 mSys	NO (LFC=2.68)	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:
- No bindings to other targets were found.
Bound By:

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

Binds To:
- No bindings to other targets were found.
Bound By:
- No bindings to other targets were found.

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

Upregulates:
- Does not upregulate other genes.
Upregulated by:
- Rv0023 (-)
Downregulates:
- Does not downregulate other genes.
Downregulated by:

Property	Value	Creator	Evidence	PMID	Comment
Interaction	Inhibition Rv0595c	shahanup86	IEP		Co-expression (Functional linkage) authors,VL. Arcus,PB. Rainey,SJ. Turner The PIN-domain toxin-antitoxin array in mycobacteria. Trends Microbiol. 2005
Interaction	Inhibition Rv0595c	shahanup86	IEP		Co-expression (Functional linkage) authors,HR. Ramage,LE. Connolly,JS. Cox Comprehensive functional analysis of Mycobacterium tuberculosis toxin-antitoxin systems: implications for pathogenesis, stress responses, and evolution. PLoS Genet. 2009
Citation	The genetic requirements for fast and slow growth in mycobacteria. authors,DJ. Beste,M. Espasa,B. Bonde,AM. Kierzek,GR. Stewart,J. McFadden PLoS ONE 2009	shahanup86	IEP	19479006	Co-expression (Functional linkage)
Interaction	Inhibition Rv0595c	shahanup86	IEP		Co-expression (Functional linkage) authors,DJ. Beste,M. Espasa,B. Bonde,AM. Kierzek,GR. Stewart,J. McFadden The genetic requirements for fast and slow growth in mycobacteria. PLoS ONE 2009
Citation	The PIN-domain toxin-antitoxin array in mycobacteria. authors,VL. Arcus,PB. Rainey,SJ. Turner Trends Microbiol. 2005	shahanup86	IEP	15993073	Co-expression (Functional linkage)
Interaction	Inhibition Rv0595c	shahanup86	IEP		Co-expression (Functional linkage) authors,VL. Arcus,PB. Rainey,SJ. Turner The PIN-domain toxin-antitoxin array in mycobacteria. Trends Microbiol. 2005
Citation	Comprehensive functional analysis of Mycobacterium tuberculosis toxin-antitoxin systems: implications for pathogenesis, stress responses, and evolution. authors,HR. Ramage,LE. Connolly,JS. Cox PLoS Genet. 2009	shahanup86	IEP	20011113	Co-expression (Functional linkage)
Interaction	Inhibition Rv0595c	shahanup86	IEP		Co-expression (Functional linkage) authors,HR. Ramage,LE. Connolly,JS. Cox Comprehensive functional analysis of Mycobacterium tuberculosis toxin-antitoxin systems: implications for pathogenesis, stress responses, and evolution. PLoS Genet. 2009
Interaction	Inhibition Rv0595c	shahanup86	IEP		Co-expression (Functional linkage) authors,DJ. Beste,M. Espasa,B. Bonde,AM. Kierzek,GR. Stewart,J. McFadden The genetic requirements for fast and slow growth in mycobacteria. PLoS ONE 2009
Symbol	VapB	jlew			Rescues growth inhibition in MS authors,BA. Ahidjo,D. Kuhnert,JL. McKenzie,EE. Machowski,BG. Gordhan,V. Arcus,GL. Abrahams,V. Mizrahi VapC toxins from Mycobacterium tuberculosis are ribonucleases that differentially inhibit growth and are neutralized by cognate VapB antitoxins. PLoS ONE 2011
Citation	VapC toxins from Mycobacterium tuberculosis are ribonucleases that differentially inhibit growth and are neutralized by cognate VapB antitoxins. authors,BA. Ahidjo,D. Kuhnert,JL. McKenzie,EE. Machowski,BG. Gordhan,V. Arcus,GL. Abrahams,V. Mizrahi PLoS ONE 2011	jlew		21738782	Rescues growth inhibition in MS
Symbol	VapB4	jlew			Relieves toxin activity. We report the heterologous toxicity of these TA loci in Escherichia coli and show that only a few of the M. tuberculosis-encoded toxins can inhibit E. coli growth and have a killing effect. This killing effect can be suppressed by coexpression of the cognate antitoxin. authors,A. Gupta Killing activity and rescue function of genome-wide toxin-antitoxin loci of Mycobacterium tuberculosis. FEMS Microbiol. Lett. 2009
Citation	Killing activity and rescue function of genome-wide toxin-antitoxin loci of Mycobacterium tuberculosis. authors,A. Gupta FEMS Microbiol. Lett. 2009	jlew		19016878	Relieves toxin activity. We report the heterologous toxicity of these TA loci in Escherichia coli and show that only a few of the M. tuberculosis-encoded toxins can inhibit E. coli growth and have a killing effect. This killing effect can be suppressed by coexpression of the cognate antitoxin.
Symbol	Vap BC-4	rslayden			Conserved hypothetical protein, highly similar in part to other M. tuberculosis hypothetical proteins e.g. Rv0626, Rv3181c, Rv3385c, Rv3407, etc.
Other	start:695228	rslayden			Conserved hypothetical protein, highly similar in part to other M. tuberculosis hypothetical proteins e.g. Rv0626, Rv3181c, Rv3385c, Rv3407, etc.
Other	stop:695485	rslayden			Conserved hypothetical protein, highly similar in part to other M. tuberculosis hypothetical proteins e.g. Rv0626, Rv3181c, Rv3385c, Rv3407, etc.
Other	strand:+	rslayden			Conserved hypothetical protein, highly similar in part to other M. tuberculosis hypothetical proteins e.g. Rv0626, Rv3181c, Rv3385c, Rv3407, etc.

TB Genome Annotation Portal