Rv2413c Family assigned · medium auto-curated
H37Rv Rv2413c · MTBC0 mtbc0_002569 ·
316 aa ·
2734619–2735569 MTBC0
(-) ·
RefSeq NP_216929.3
Genomic neighbourhood (genome browser)
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Annotation: from legacy to revised
| Legacy (H37Rv / Mycobrowser) | hypothetical protein |
|---|---|
| MTBC0 PGAP re-annotation | DNA polymerase III subunit delta |
| Revised (this work) | DNA polymerase III subunit delta. Pfam: DNA_pol3_delta_C (PF21694.3). |
| Functional category (TubercuList) | conserved hypotheticals |
Auto-curated: this verdict and function were generated by rules from PGAP + Pfam + Foldseek and have not been hand-reviewed.
In the literature (TB corpus sweep) cited only under an ortholog name
Found under: M. leprae (2).
2 TB publications mention this gene. Invisible under its H37Rv locus tag: this gene appears in the literature ONLY under its ortholog identifier(s) (M. leprae). Searching 'Rv2413c' alone finds nothing.
| Publication | Date |
|---|---|
| Studies of lipoproteins of Mycobacterium leprae. doi:10.5025/hansen.73.15 | 2004 |
| Novel 33-kilodalton lipoprotein from Mycobacterium leprae. doi:10.1128/IAI.70.8.4106-4111.2002 | 2002 |
This layer CITES the literature, it does not change the verdict or the function. A gene may be heavily studied (as an antigen, a resistance determinant, a drug target) while its molecular function is settled elsewhere in the fiche. This distinguishes a gene that is dark because nobody has looked from one that is dark despite having been studied. Source: PubMed (whole), MULTI-ALIAS sweep: H37Rv locus tag AND every ortholog identifier (M. bovis Mb…, M. marinum MMAR_…, M. smegmatis MSMEG_…, M. leprae ML…, M. abscessus MAB_…), each hit VERIFIED against the abstract text (word-boundary regex). phase73/phase75, 2026-07-13.
CRISPRi vulnerability
Vulnerability index -0.30 (95% CI -0.47 to -0.13). A more negative index = more vulnerable to knockdown (better drug-target quality); indicative threshold VI ≤ -6 = highly vulnerable.
Quantitative CRISPRi knockdown, graded (finer than binary Tn-seq essentiality). Source: CRISPRi vulnerability index (Bosch 2021, pebble.rockefeller.edu).
Legacy record & comparison (Mycobrowser) ahead of Mycobrowser
| Mycobrowser function | Function unknown |
|---|
Mycobrowser classes this locus among conserved hypotheticals; the atlas now assigns a functional handle (curated function (UniProt), EC number, COG category). Mycobrowser is no longer maintained, so its EC numbers predate recent nomenclature revisions (e.g. the 2018 EC 7 "translocase" class) — most EC differences are re-numberings of the same enzyme, not conflicts.
Orthologues (reciprocal best hits across mycobacteria)
| M. bovis |
Mb2436c
· 99.7% identity |
|---|---|
| M. leprae |
ML0603
· 83.9% identity |
| M. marinum |
MMAR_3734
· 84.3% identity |
| M. smegmatis |
MSMEG_4572
· 78.5% identity |
| M. orygis |
RJtmp_002495
· 99.7% identity |
| M. abscessus |
MAB_1633
· 70.4% identity |
Reciprocal-best-hit orthologues (DIAMOND) against the Mycobrowser reference proteomes. A missing species is informative: e.g. a gene absent from M. leprae was likely lost in its reductive genome evolution. Locus tags link to Mycobrowser.
Curated reference (UniProt)
| UniProt |
P71730
SwissProt · reviewed
· Evidence at protein level
|
|---|---|
| UniProt name | Probable DNA polymerase III subunit delta |
| EC (curated) |
EC 2.7.7.7
|
| Curated function | DNA polymerase III is a complex, multichain enzyme responsible for most of the replicative synthesis in bacteria. Pol III also exhibits 3'-5' exonuclease activity. The delta subunit interacts with the gamma/tau subunit to load the beta sliding clamp (dnaN) onto the DNA (By similarity). |
Functional vocabulary (eggNOG-mapper, orthology transfer)
| COG category |
L Replication, recombination and repair
|
|---|---|
| Preferred name | holA |
| eggNOG description | DNA polymerase III, delta |
| Orthologous group | COG1466 |
| EC number |
EC 2.7.7.7
|
| KEGG orthology |
K02340
|
| KEGG pathways |
map00230, map00240, map01100, map03030, map03430, map03440
|
| KEGG modules |
M00260
|
Orthology-based transfer (eggNOG 5.0.2, diamond). EC/KO/GO/CAZy are computed annotations, not manual curation; cross-check against the primary literature before treating a specific reaction as established.
Conservation & selection (intra-MTBC, 145 209 strains)
| pN/pS | 1.487 · diversifying/relaxed |
|---|---|
| Polymorphic sites (≥ 0.1% of strains) | 1 synonymous, 4 missense, 0 nonsense, 0 frameshift |
pN/pS from segregating SNPs (singletons removed) normalised by possible sites. Low pN/pS = purifying selection (a strong signal that a "hypothetical" is a real, constrained gene). A high pN/pS is ambiguous: relaxed constraint or positive selection (drug resistance, antigenic variation) inflate it; e.g. rpoB/katG/pncA score high here for resistance, not loss of function. A clonal disruption (one allele over a clade) suggests lineage pseudogenisation; a convergent one (many independent alleles) is typical of resistance loss-of-function.
Outgroup conservation (beyond the MTBC) Actinomycetia
| M. canettii dN/dS (deep-divergence selection) |
0.0 (low power)
· 2 consensus substitution(s) low power (2 canettii-consensus substitution(s)); present in M. canettii but dN/dS not reliable |
|---|---|
| Genus-wide presence (~53 non-MTBC Mycobacterium) |
present in 53/53 (100%) · mean identity 84.4%
· 4/4 closest MTBAP relatives conserved across the genus (present in 53/53 non-MTBC Mycobacterium genomes, incl. distant relatives) — an ancient core gene predating the genus radiation |
| Phylostratum (deepest detected homolog) |
MTBC-specific → Mycobacterium → Mycobacteriaceae → Corynebacteriales → Actinomycetia → Bacteria detected in 10/13 non-Mycobacterium reference genomes (down to Actinomycetia) · mean identity 50.4% detected across the class Actinomycetia (beyond Corynebacteriales) but not outside the phylum — an Actinobacteria-level ancient gene |
Two orthogonal outgroup signals. M. canettii (the immediate outgroup) gives a deep-divergence dN/dS (a low value confirms a constrained, real gene; shown as confident only at ≥8 substitutions, else flagged low-power). Genus-wide presence/absence (tblastn vs assembled non-MTBC genomes) places the gene on the ancient-core ↔ MTBC-specific axis: a gene absent even from the closest MTBAP relatives is a candidate MTBC-specific innovation (possible host-adaptation factor, to confirm by synteny). The phylostratum extends that axis outside the genus (tblastn vs 13 reference genomes spanning Mycobacteriaceae → Corynebacteriales → Actinomycetia → outside the phylum): it is the deepest clade in which a homolog is still detected, i.e. a proxy for gene age. Read it with the null model in mind: a shallow (young) stratum can also reflect homology-detection failure for short or fast-evolving ORFs, so it is a descriptive axis, not a proof of novelty.
Essentiality (transposon mutagenesis) essential
| DeJesus 2017 call | ES · essential |
|---|---|
| What the call means | essential: insertions absent across the whole ORF |
| TA sites (Himar1) | 13 in the ORF — 13 in the essential state, 0 growth-defect, 0 non-essential, 0 growth-advantage. Saturation 0.000, mean read count 0. A region of the protein devoid of TA sites is invisible to this assay: nothing can be inferred about it, in either direction. |
Genome-wide Himar1 transposon essentiality in H37Rv (DeJesus 2017). An essential call (ES/ESD/GD) is strong, independent evidence that a "hypothetical" locus encodes a functional, selectively required gene — orthogonal to intra-species conservation.
Chemical-genetic target & druggability (PROSPECT) hypomorph tool strain
This gene is part of the PROSPECT collection of TetON transcriptional-knockdown (hypomorph) strains of essential M. tuberculosis genes, built as a sensitised background for chemical-genetic mechanism-of-action deconvolution. Being in the panel means the gene is an essential / vulnerable target for which a validated knockdown tool strain exists.
| Hypomorph strain | Rv2413c-_TetOn18.1 (TetON promoter 18) |
|---|---|
| Baseline knockdown fitness | 2.541 median doublings (across 6 screen pool(s)) — fewer doublings = stronger growth defect on knockdown |
| Used in target deconvolution | yes (informs phenotypic-cluster / MOA assignment) |
Panel membership reflects essentiality/vulnerability and the availability of a genetic tool, not a specific molecular function; it never changes the verdict here. Source: Bond AN et al., Nat Commun 2025;16:9673 (doi:10.1038/s41467-025-64662-x); PROSPECT chemical-genetic platform.
Proteomics (mass spectrometry) detected
| MS detection | detected in 9 of 16 independent MS datasets |
|---|---|
| Integrated abundance | 18.9 ppm · rank 2375/3519 (32.5th percentile) |
Detection by mass spectrometry is direct, experimental evidence that the protein product exists — orthogonal to sequence conservation and to Tn-seq essentiality, and especially decisive for a "hypothetical" locus. Reproducible detection across several independent datasets (PaxDb) makes the existence claim robust; the integrated abundance places the protein in the proteome's dynamic range.
Physico-chemical properties (computed, ProtParam)
| Length | 316 aa |
|---|---|
| Molecular weight | 33.1 kDa |
| Theoretical pI | 5.83 |
| GRAVY | 0.053 (hydrophobic) |
| Aliphatic index | 98.9 |
| Aromaticity | 0.035 |
| Instability index | 33.1 (stable) |
Computed from the ancestral MTBC0 sequence with the ExPASy ProtParam method (Biopython). Descriptive biophysical context: a positive GRAVY flags a hydrophobic (often membrane) protein, a high instability index (>40) predicts a short in-vitro half-life, an extreme pI hints at compartment or binding partner.
Domains (Pfam, hmmscan --cut_ga)
| Pfam | Accession | i-Evalue | Residues | Description |
|---|---|---|---|---|
DNA_pol3_delta_C | PF21694.3 | 2.7e-08 | 193–304 | DNA polymerase III delta subunit, C-terminal domain |
Structural search (AlphaFold DB model, Foldseek vs PDB — genome-wide) pLDDT 90.5
| PDB hit | prob | TM-score | E-value | Description |
|---|---|---|---|---|
3zh9-assembly1_B |
1.00 | 0.65 | 3.1e-11 sig | 3zh9-assembly1_B Bacillus subtilis DNA clamp loader delta protein (YqeN) |
3glh-assembly3_K |
1.00 | 0.69 | 2.7e-08 sig | 3glh-assembly3_K Crystal Structure of the E. coli clamp loader bound to Psi Peptide |
8vap-assembly1_A |
1.00 | 0.52 | 9.6e-09 sig | 8vap-assembly1_A Structure of the E. coli clamp loader bound to the beta clamp in a Fully-Open conformation |
1jqj-assembly1_C |
1.00 | 0.51 | 1.5e-08 sig | 1jqj-assembly1_C Mechanism of Processivity Clamp Opening by the Delta Subunit Wrench of the Clamp Loader Complex of E. coli DNA Polymerase III: Structure of the beta-delta complex |
3glf-assembly2_G |
1.00 | 0.54 | 7.0e-08 sig | 3glf-assembly2_G Crystal Structure of the Ecoli Clamp Loader Bound to Primer-Template DNA |
Foldseek search of the AlphaFold DB model (mean pLDDT 90.5, gated at 70) against the PDB — a genome-wide extension of the ESMFold dark-gene search that also covers proteins beyond the single-sequence length limit. Confident structural neighbours (E < 0.01) shown.
Genomic context (neighbours & predicted operon) operon of 3
| Upstream (5' on genome) | rpsT (+ strand, 15 bp gap) |
|---|---|
| Downstream (3' on genome) | Rv2414c (- strand, 30 bp gap) |
| Predicted operon |
Rv2413c · Rv2414c · Rv2415c
|
Neighbours from the H37Rv annotation (- strand). The operon is predicted by co-directional intergenic distance (same strand, gaps ≤50 bp) — a transcription-unit hypothesis, not a mapped TSS. For a "hypothetical", co-transcription with a characterised operon is a concrete functional lead (complements the STRING neighborhood channel below).
Functional interaction network (STRING v12, guilt-by-association)
Explore full network →Node colour = verdict, dashed = hypothetical; edge colour = evidence (green experimental, orange genomic-context, grey co-expression), width ∝ score. Click a partner to open its page; "Explore full network" to walk the graph.
Closest characterised functional partner: Rv3644c (DNA polymerase), high confidence from genomic context alone (score 995 excluding text-mining). This association is the citable seed of a function hypothesis for this hypothetical protein.
| Partner | Product | Score | No text-mining | Channels (≥400) |
|---|---|---|---|---|
Rv3644c exp |
DNA polymerase | 995 | 995 ctx | cooccurence:690 experimental:829 database:900 |
Rv0002 dnaN exp |
DNA polymerase III subunit beta | 989 | 988 | experimental:829 database:900 |
Rv3721c dnaZX exp |
DNA polymerase III subunit gamma/tau | 987 | 986 | experimental:829 database:900 |
Rv1547 dnaE1 exp |
DNA polymerase III subunit alpha | 988 | 985 | experimental:829 database:900 |
Rv2191 hyp exp |
hypothetical protein | 966 | 944 | experimental:442 database:900 textmining:413 |
Rv3711c dnaQ exp |
DNA polymerase III subunit epsilon | 948 | 942 | experimental:442 database:900 |
Rv2414c hyp |
hypothetical protein | 888 | 880 ctx | neighborhood:839 |
Rv3370c dnaE2 exp |
error-prone DNA polymerase | 895 | 857 | experimental:829 |
Rv2116 lppK exp |
lipoprotein LppK | 851 | 832 | experimental:829 |
Rv2415c hyp |
hypothetical protein | 836 | 830 ctx | neighborhood:829 |
Rv2050 rbpA |
RNA polymerase-binding protein RbpA | 769 | 769 ctx | cooccurence:769 |
Rv2708c hyp |
hypothetical protein | 760 | 761 ctx | cooccurence:759 |
Rv2680 hyp |
hypothetical protein | 738 | 739 ctx | cooccurence:738 |
Rv2146c |
transmembrane protein | 742 | 726 ctx | cooccurence:719 |
Rv2219 |
transmembrane protein | 725 | 726 ctx | cooccurence:725 |
STRING combines evidence channels (neighborhood, fusion, cooccurrence, coexpression, experimental, database, text-mining) into a 0–1000 score. The ctx badge marks edges carried by the genomic-context channels (conserved neighborhood, fusion, phylogenetic co-occurrence), which are independent of orthology and structure and the strongest signal for an unknown gene. The exp badge marks an experimentally-supported partner (measured interaction, experimental/database channel ≥400) as opposed to a purely predicted one — but note that the M. tuberculosis experimental interactome is dominated by a noisy bacterial-two-hybrid screen, so a strong measured link that contradicts the operon/localisation context is likely a false positive. The no text-mining column recomputes the score from data alone, so a link that does not depend on the literature is visible. Association is a function hypothesis, not proof: corroborate with the operon context and the primary literature before assigning a function.
Evidence
- Legacy H37Rv annotation: hypothetical protein
- MTBC0 PGAP product: DNA polymerase III subunit delta
- Pfam (hmmscan --cut_ga): DNA_pol3_delta_C PF21694.3 (E=3e-08)
- (auto-curated by rules from PGAP + Pfam + Foldseek; not hand-reviewed)
Sources
- Ancestral sequence & coordinates: Harrison LB et al. (2024), An imputed ancestral reference genome for the MTBC, doi:10.1101/2023.09.07.556366
- Product annotation: NCBI PGAP on MTBC0; legacy from H37Rv NC_000962.3 (RefSeq NP_216929.3)
- Domains: Pfam-A via hmmscan --cut_ga — DNA_pol3_delta_C (PF21694.3)
- Sequence-level signal: ESM Atlas (EvolutionaryScale × BioHub) — exploratory
- Controlled vocabulary: eggNOG-mapper 2.1.12 (Cantalapiedra et al. 2021,
doi:10.1093/molbev/msab293), eggNOG 5.0 DB
(Huerta-Cepas et al. 2019) — OG
COG1466 - Curated reference: UniProt P71730 (SwissProt, reviewed; Evidence at protein level)
- Intra-MTBC selection: pN/pS and disruption from SPDI variants of 145 209 MTBC strains (this work, local collection vs H37Rv NC_000962.3)
- Genome-wide structure: AlphaFold DB model (Jumper et al. 2021, doi:10.1038/s41586-021-03819-2; Varadi et al. 2024, doi:10.1093/nar/gkad1011) searched vs PDB with Foldseek (mean pLDDT 90.5)
- Interaction network: STRING v12.0 (Szklarczyk et al. 2023,
doi:10.1093/nar/gkac1000), taxon 83332, CC-BY 4.0 —
82 functional partner(s); context anchor
Rv3644c - Essentiality: genome-wide transposon mutagenesis in H37Rv — DeJesus et al. 2017 (mBio, doi:10.1128/mBio.02133-16, CC BY)
- Proteomics: integrated mass-spectrometry abundance from PaxDb 5.0 (Huang et al. 2023, doi:10.1016/j.mcpro.2023.100640), taxon 83332 — weighted average of 16 datasets, incl. Schubert et al. 2013 (doi:10.1016/j.chom.2013.04.008) and Albrethsen et al. 2013 (doi:10.1074/mcp.M112.018846)
- Functional category: TubercuList scheme (Cole et al. 1998, doi:10.1038/31159), via Mycobrowser (Kapopoulou et al. 2011, doi:10.1016/j.tube.2010.09.006)
- Orthologues: reciprocal best hits (DIAMOND, Buchfink et al. 2021, doi:10.1038/s41592-021-01101-x) against Mycobrowser release 5 reference proteomes
- Genomic context / operon: H37Rv annotation; operon predicted by co-directional intergenic distance (Salgado et al. 2000, doi:10.1073/pnas.030539397)
- Physico-chemical properties: ExPASy ProtParam method via Biopython (Gasteiger et al. 2005), computed from the MTBC0 sequence
- Primary literature: none located yet; annotation rests on the domain/homology sources above.
Ancestral MTBC0 protein sequence
>mtbc0_002569|Rv2413c| MHLVLGDEELLVERAVADVLRSARQRAGTADVPVSRMRAGDVGAYELAELLSPSLFAEERIVVLGAAAEAGKDAAAVIESAAADLPAGTVLVVVHSGGGRAKSLANQLRSMGAQVHPCARITKVSERADFIRSEFASLRVKVDDETVTALLDAVGSDVRELASACSQLVADTGGAVDAAAVRRYHSGKAEVRGFDIADKAVAGDVAGAAEALRWAMMRGEPLVVLADALAEAVHTIGRVGPQSGDPYRLAAQLGMPPWRVQKAQKQARRWSRDTVATAMRLVAELNANVKGAVADADYALESAVRQVAELVADRGR
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