Rv0450c (mmpL4)

Current annotations:
- TBCAP: (community-based annotations - see table at bottom of page)
- TBDB: transmembrane transporter mmpL4
- REFSEQ: transmembrane transport protein MmpL4
- PATRIC: Transmembrane transport protein MmpL4
- TUBERCULIST: Probable conserved transmembrane transport protein MmpL4
- NCBI: Probable conserved transmembrane transport protein MmpL4
- updated information (H37Rv4):
  - gene name: mmpL4
  - function: mycobactin export
  - reference: Wells 2013; PMC3561183
Type: Essential
Start: 538588
End: 541491
Operon:

Trans-membrane region:
Role: II.C.4 - Conserved membrane proteins
GO terms:
- GO:0044119 - growth of symbiont in host cell (Uniprot)
- GO:0040007 - growth (Uniprot)
- GO:0016021 - integral component of membrane (Uniprot)
- GO:0016020 - membrane (Uniprot)
- GO:0009405 - pathogenesis (Uniprot)
- GO:0005886 - plasma membrane (Uniprot)
- GO:0005618 - cell wall (Uniprot)
- GO:0005576 - extracellular region (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): (none with >35% aa id)
Links to additional information on mmpL4:
- TBDB (updated)
- Phyre2 structure prediction, model: final.casp.pdb (from Mao et al, 2013)
- UniProt
- AlphaFold model
- Vulnerability = 1.423 (from Jeremy Rock's lab)
- KEGG - nucleotide and amino acid sequences of gene
- Mycobrowser
- PATRIC
- BioCyc
- Systems Biology

Amino Acid Sequence

VSTKFANDSNTNARPEKPFIARMIHAFAVPIILGWLAVCVVVTVFVPSLEAVGQERSVSLSPKDAPSFEAMGRIGMVFKEGDSDSFAMVIIEGNQPLGDA
AHKYYDGLVAQLRADKKHVQSVQDLWGDPLTAAGVQSNDGKAAYVQLSLAGNQGTPLANESVEAVRSIVESTPAPPGIKAYVTGPSALAADMHHSGDRSM
ARITMVTVAVIFIMLLLVYRSIITVVLLLITVGVELTAARGVVAVLGHSGAIGLTTFAVSLLTSLAIAAGTDYGIFIIGRYQEARQAGEDKEAAYYTMYR
GTAHVILGSGLTIAGATFCLSFARMPYFQTLGIPCAVGMLVAVAVALTLGPAVLHVGSRFGLFDPKRLLKVRGWRRVGTVVVRWPLPVLVATCAIALVGL
LALPGYKTSYNDRDYLPDFIPANQGYAAADRHFSQARMKPEILMIESDHDMRNPADFLVLDKLAKGIFRVPGISRVQAITRPEGTTMDHTSIPFQISMQN
AGQLQTIKYQRDRANDMLKQADEMATTIAVLTRMHSLMAEMASTTHRMVGDTEEMKEITEELRDHVADFDDFWRPIRSYFYWEKHCYGIPICWSFRSIFD
ALDGIDKLSEQIGVLLGDLREMDRLMPQMVAQIPPQIEAMENMRTMILTMHSTMTGIFDQMLEMSDNATAMGKAFDAAKNDDSFYLPPEVFKNKDFQRAM
KSFLSSDGHAARFIILHRGDPQSPEGIKSIDAIRTAAEESLKGTPLEDAKIYLAGTAAVFHDISEGAQWDLLIAAISSLCLIFIIMLIITRAFIAAAVIV
GTVALSLGASFGLSVLLWQHILAIHLHWLVLAMSVIVLLAVGSDYNLLLVSRFKQEIGAGLKTGIIRSMGGTGKVVTNAGLVFAVTMASMAVSDLRVIGQ
VGTTIGLGLLFDTLIVRSFMTPSIAALLGRWFWWPLRVRSRPARTPTVPSETQPAGRPLAMSSDRLG

(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)	1.39 (0.3)	1.02 (0.53)
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

Rv0450c/mmpL4, gene len: 2903 bp, num TA sites: 84

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	essential	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	uncertain	M9 minimal+glycerol	Gumbel	2 replicates; Padj<0.05
in-vitro (cholesterol)	Griffin 2011 PPath	uncertain	M9 minimal+cholesterol	Gumbel	3 replicates; Padj<0.05
differentially essential in cholesterol	Griffin 2011 PPath	YES (LFC=-2.36)	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	YES (LFC=-1.822)	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=-0.2)	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:
- Rv0023 (-)
- Rv3849 (espR)

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

Binds To:
- No bindings to other targets were found.
Bound By:
- Rv0135c (-) (Direct binding)
- Rv1776c (-) (Direct binding)
- Rv0678 (-) (Upstream of operon)
- Rv1049 (-) (Upstream of operon)
- Rv2250c (-) (Upstream of operon)
- Rv3676 (crp) (Upstream of operon)

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:
- Rv0023 (-)
- Rv3849 (espR)

Property	Value	Creator	Evidence	PMID	Comment
Interaction	Regulatory Rv2711	priyadarshinipriyanka2001	IEP		G. Lamichhane, S. Tyagi et al. Designer arrays for defined mutant analysis to detect genes essential for survival of Mycobacterium tuberculosis in mouse lungs. Infect. Immun. 2005
Citation	Identification of a virulence gene cluster of Mycobacterium tuberculosis by signature-tagged transposon mutagenesis. authors,LR. Camacho,D. Ensergueix,E. Perez,B. Gicquel,C. Guilhot Mol. Microbiol. 1999	priyadarshinipriyanka2001	IEP	10564470	None
Interaction	Regulatory Rv2711	priyadarshinipriyanka2001	IEP		authors,LR. Camacho,D. Ensergueix,E. Perez,B. Gicquel,C. Guilhot Identification of a virulence gene cluster of Mycobacterium tuberculosis by signature-tagged transposon mutagenesis. Mol. Microbiol. 1999
Citation	ideR, An essential gene in mycobacterium tuberculosis: role of IdeR in iron-dependent gene expression, iron metabolism, and oxidative stress response. GM. Rodriguez, MI. Voskuil et al. Infect. Immun. 2002	priyadarshinipriyanka2001	IEP	12065475	None
Interaction	Regulatory Rv2711	priyadarshinipriyanka2001	IEP		GM. Rodriguez, MI. Voskuil et al. ideR, An essential gene in mycobacterium tuberculosis: role of IdeR in iron-dependent gene expression, iron metabolism, and oxidative stress response. Infect. Immun. 2002
Citation	Contribution of the Mycobacterium tuberculosis MmpL protein family to virulence and drug resistance. P. Domenech, MB. Reed et al. Infect. Immun. 2005	priyadarshinipriyanka2001	IEP	15908378	None
Interaction	Regulatory Rv2711	priyadarshinipriyanka2001	IEP		P. Domenech, MB. Reed et al. Contribution of the Mycobacterium tuberculosis MmpL protein family to virulence and drug resistance. Infect. Immun. 2005
Citation	Designer arrays for defined mutant analysis to detect genes essential for survival of Mycobacterium tuberculosis in mouse lungs. G. Lamichhane, S. Tyagi et al. Infect. Immun. 2005	priyadarshinipriyanka2001	IEP	15784600	None
Interaction	RegulatedBy Rv2711	yamir.moreno	IEP		Microarrays. mRNA levels of regulated element measured and compared between wild-type and trans-element mutation (knockout, over expression etc.) performed by using microarray (or macroarray) experiments.. GM. Rodriguez, MI. Voskuil et al. ideR, An essential gene in mycobacterium tuberculosis: role of IdeR in iron-dependent gene expression, iron metabolism, and oxidative stress response. Infect. Immun. 2002

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