Rv1818c (PE_PGRS33)

Current annotations:
- TBCAP: (community-based annotations - see table at bottom of page)
- TBDB: PE-PGRS family protein
- REFSEQ: PE-PGRS family protein
- PATRIC: PE family protein
- TUBERCULIST: PE-PGRS family protein PE_PGRS33
- NCBI: PE-PGRS family protein PE_PGRS33
- updated information (H37Rv4):
  - gene name: PE_PGRS33
  - function:
  - reference:
Type: Conditional
Start: 2061178
End: 2062674
Operon:

Trans-membrane region:
Role: IV.C.1.b - PE_PGRS subfamily
GO terms:
- GO:0070482 - response to oxygen levels (Uniprot)
- GO:0052167 - modulation by symbiont of host innate immune response (Uniprot)
- GO:0046789 - host cell surface receptor binding (Uniprot)
- GO:0044650 - adhesion of symbiont to host cell (Uniprot)
- GO:0042594 - response to starvation (Uniprot)
- GO:0016020 - membrane (Uniprot)
- GO:0009986 - cell surface (Uniprot)
- GO:0009405 - pathogenesis (Uniprot)
- GO:0009279 - cell outer membrane (Uniprot)
- GO:0005618 - cell wall (Uniprot)
- GO:0005576 - extracellular region (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): (none with >35% aa id)
Links to additional information on PE_PGRS33:
- TBDB (updated)
- Phyre2 structure prediction, model: final.casp.pdb (from Mao et al, 2013)
- UniProt
- AlphaFold model
- Vulnerability = 0.14 (from Jeremy Rock's lab)
- KEGG - nucleotide and amino acid sequences of gene
- Mycobrowser
- PATRIC
- BioCyc
- Systems Biology

Amino Acid Sequence

MSFVVTIPEALAAVATDLAGIGSTIGTANAAAAVPTTTVLAAAADEVSAAMAALFSGHAQAYQALSAQAALFHEQFVRALTAGAGSYAAAEAASAAPLEG
VLDVINAPALALLGRPLIGNGANGAPGTGANGGDGGILIGNGGAGGSGAAGMPGGNGGAAGLFGNGGAGGAGGNVASGTAGFGGAGGAGGLLYGAGGAGG
AGGRAGGGVGGIGGAGGAGGNGGLLFGAGGAGGVGGLAADAGDGGAGGDGGLFFGVGGAGGAGGTGTNVTGGAGGAGGNGGLLFGAGGVGGVGGDGVAFL
GTAPGGPGGAGGAGGLFGVGGAGGAGGIGLVGNGGAGGSGGSALLWGDGGAGGAGGVGSTTGGAGGAGGNAGLLVGAGGAGGAGALGGGATGVGGAGGNG
GTAGLLFGAGGAGGFGFGGAGGAGGLGGKAGLIGDGGDGGAGGNGTGAKGGDGGAGGGAILVGNGGNGGNAGSGTPNGSAGTGGAGGLLGKNGMNGLP

(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)	1.56 (0.48)	1.41 (0.73)
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

Rv1818c/PE_PGRS33, gene len: 1496 bp, num TA sites: 17

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	non-essential	7H9	TRASH	essential if hybridization ratio<0.2
in-vivo (mice)	Sassetti 2003 PNAS	non-essential	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	non-essential	M9 minimal+cholesterol	Gumbel	3 replicates; Padj<0.05
differentially essential in cholesterol	Griffin 2011 PPath	NO (LFC=-0.61)	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=0.161)	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, cofactors)
differentially essential in YM rich medium	Minato 2019 mSys	NO (LFC=-0.51)	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:
- Rv0081 (-)
- Rv1167c (-)

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

Binds To:
- No bindings to other targets were found.
Bound By:
- Rv0691c (-) (Direct binding)
- Rv0967 (csoR) (Direct binding)
- Rv3133c (devR) (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:
- Rv0081 (-)
- Rv1167c (-)

Property	Value	Creator	Evidence	PMID	Comment
Interaction	PhysicalInteraction Rv2250c	sourish10	IPI		Yeast two-hybrid (Physical interaction) J. Zeng, L. Zhang et al. Over-producing soluble protein complex and validating protein-protein interaction through a new bacterial co-expression system. Protein Expr. Purif. 2010
Interaction	RegulatedBy Rv2710	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.. JH. Lee, PC. Karakousis et al. Roles of SigB and SigF in the Mycobacterium tuberculosis sigma factor network. J. Bacteriol. 2008
Citation	Functional dissection of the PE domain responsible for translocation of PE_PGRS33 across the mycobacterial cell wall. authors,A. Cascioferro,MH. Daleke,M. Ventura,V. Don,G. Delogu,G. Pal,W. Bitter,R. Manganelli PLoS ONE 2011	jlew		22110736	In this paper, we characterize the PE domain of PE_PGRS33 (PERv1818c), one of the best characterized PE proteins. We confirmed that the PE domain is essential for PE_PGRS33 surface localization. Using Mycobacterium marinum we could show that the type VII secretion system ESX-5 is essential for PE_PGRS33 export.
Citation	Over-producing soluble protein complex and validating protein-protein interaction through a new bacterial co-expression system. J. Zeng, L. Zhang et al. Protein Expr. Purif. 2010	jlew		19747546	Rv2250c and Rv1818c interact. Using an in vivo pull-down assay, for the first time we have confirmed the presence of three pairs of PE/PPE-related novel protein interactions in this pathogen.
Citation	A comparative study of host response to three Mycobacterium tuberculosis PE_PGRS proteins. PP. Singh, M. Parra et al. Microbiology (Reading, Engl.) 2008	jlew		18957600	More persistent. Overexpress in MS and infect macrophages and mice.
Citation	PE is a functional domain responsible for protein translocation and localization on mycobacterial cell wall. A. Cascioferro, G. Delogu et al. Mol. Microbiol. 2007	jlew		18028308	Protein is surface exposed and localizes in the cell wall. PE domain for cell wall localization
Citation	PE_PGRS proteins are differentially expressed by Mycobacterium tuberculosis in host tissues. G. Delogu, M. Sanguinetti et al. Microbes Infect. 2006	jlew		16798044	in axenic cultures, significant up-regulation occurring at late log and early stationary phases. quantitative real-time RT-PCR (QRT-PCR) was implemented to assess expression of three PE_PGRS genes under different experimental conditions.
Citation	Variable expression patterns of Mycobacterium tuberculosis PE_PGRS genes: evidence that PE_PGRS16 and PE_PGRS26 are inversely regulated in vivo. V. Dheenadhayalan, G. Delogu et al. J. Bacteriol. 2006	jlew		16672626	Constitutively expressed in all in vitro conditions examined. Evaluation of expression of 16 PE_PGRS genes present in Mycobacterium tuberculosis under various growth conditions

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