Rv2261c Family assigned · low auto-curated · to review

H37Rv Rv2261c · MTBC0 · 140 aa · 2534042–2534464 H37Rv (-) · RefSeq

Genomic neighbourhood (genome browser)

This gene (outlined) in its genomic context; arrows are neighbouring genes coloured by verdict. Click any gene to navigate. Pan and zoom in the full browser.

Annotation: from legacy to revised

Legacy (H37Rv / Mycobrowser)	Conserved hypothetical protein
MTBC0 PGAP re-annotation	—
Revised (this work)	Transfers the fatty acyl group on membrane lipoproteins
Functional category (TubercuList)	lipid metabolism

Curation note: Added P16.5d: Mycobrowser-annotated gene absent from RefSeq NC_000962.3 (the atlas' original 3906-CDS reference). Foundation record from the Mycobrowser release + translated H37Rv sequence; heavy enrichment layers (structure, orthology, conservation, interaction) pending. P16.23 (phase135, 2026-08-17): couche tss ajoutee (leaderless=False).

Auto-curated: this verdict and function were generated by rules from PGAP + Pfam + Foldseek and have not been hand-reviewed (flagged for human review).

In the literature (TB corpus sweep)

Named in the body of 1 paper(s) in Europe PMC full text, though in no title or abstract. Matched under Rv2261c (1).

A hit does NOT mean functional characterisation -- it may be a mention in a genome-wide table or screen (e.g. a differential-expression supplementary table), exactly the mechanism that revealed the Rv3222c/Sarkar2021 co-induction. Restricted to hits CORROBORATED by the H37Rv tag itself, the gene name, or a substantial/multi-alias hit count -- single-low-count-ortholog-only hits were excluded pending individual review (cf. Rv0027/Mb0028, a confirmed collision unrelated to Mycobacterium). Coverage limit (P52.4, measured 2026-09-30): the body-text part of this search only sees articles whose full text Europe PMC holds, about 8-13 % of the TB literature published before 2005, 21 % for 2005-2009, 40 % for 2010-2014 and 66 % since 2020, so the absence of a hit says little about older mentions.

This distinguishes a gene that is dark because nobody has looked from one that is dark despite having been studied. Source: .

CRISPRi vulnerability

Vulnerability index 0.59 (95% CI -2.31 to 4.42). 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, supplementary Table S2 'mmc3.xlsx', bulk import via Europe PMC -- supersedes the per-gene pebble.rockefeller.edu scrape of phase46_crispri_vulnerability.py).

Caveat on this estimate. Bosch et al. flag this gene's vulnerability estimate as NOT certain, and here that call has a mechanical cause visible in the library itself: every guide targeting this gene is >=21 nt (str_span=0.279 on a 0-1 scale, near the genome floor), and guide repression strength saturates from 21 nt on -- so the library never sampled a partial knockdown for this gene, only the near-maximal repression plateau. The dose-response fit (and this VI) is therefore essentially unconstrained by data, not merely uncertain -- a limitation of the CRISPRi library design for the non-essential class (Bosch et al. 2021), not a defect in this specific measurement. n_guides=7 is descriptive only and does not predict this. Do not cite this VI as a standalone vulnerability claim.

Legacy record & comparison (Mycobrowser)

Mycobrowser function	Function unknown; thought to be involved in lipid metabolism.

The legacy Mycobrowser record is shown for verification. Mycobrowser is no longer maintained; its EC numbers predate recent nomenclature revisions, so a class change usually reflects re-numbering, not a conflict.

Curated reference (UniProt)

UniProt	`I6XDW5` TrEMBL · unreviewed
UniProt name	CN hydrolase domain-containing protein

Functional vocabulary (eggNOG-mapper, orthology transfer)

COG category	`M` Cell wall / membrane / envelope biogenesis
Preferred name	lnt
eggNOG description	Transfers the fatty acyl group on membrane lipoproteins
Orthologous group	`COG0815`
KEGG orthology	`ko:K03820`
CAZy family	`GT2`

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, 142 601 strains, snapshot of 2026-09-29)

pN/pS	0.174 · quasi-invariant (3 sites), pN/pS underpowered
Polymorphic sites (≥ 0.1% of strains)	2 synonymous, 1 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.

Essentiality (transposon mutagenesis)

DeJesus 2017 call	NE · non-essential
What the call means	non-essential
TA sites (Himar1)	7 in the ORF — 0 in the essential state, 0 growth-defect, 7 non-essential, 0 growth-advantage. Saturation 1.000, mean read count 123.571428571. A region of the protein devoid of TA sites is invisible to this assay: nothing can be inferred about it, in either direction. All 7 sites lie in this ORF alone (no overlapping CDS shares any), so the call is attributable to this gene.
Caveat	Read with some caution: only 7 TA (Himar1) sites in the whole ORF (atlas median 13). The DeJesus 2017 call rests on fewer independent observations than for a longer gene. If this gene overlaps a neighbour (see Genomic-neighbour overlap section below), some of these 7 sites may fall inside the neighbour's ORF rather than its own, leaving even fewer truly informative sites than the raw count suggests. (P20.3)

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.

Proteomics (mass spectrometry) not detected

Not detected in the mass-spectrometry datasets integrated by PaxDb. This is not evidence of absence, and this atlas can say which bias dominates, because it measured it on its own 482 undetected proteins. Size is the main factor: undetected proteins have a median length of 145 aa against 295 aa for detected ones, and 25.3 % of them are shorter than 100 aa against 6.0 %. Predicted localisation matters far less than usually assumed: detection rates are 89.3 % for globular, 84.9 % for transmembrane, 88.0 % for lipoproteins and 77.8 % for signal-peptide proteins — so a short protein is under-sampled whatever its predicted compartment, and hydrophobicity alone is a weak excuse. Condition-specific expression and few tryptic peptides (PE/PPE repeats) add to this.

Predicted localisation (DeepTMHMM + lipobox)

Prediction	predicted membrane protein (1 TM helix)
DeepTMHMM class	TM
TM helices (DeepTMHMM)	1

Transmembrane topology and signal peptide from DeepTMHMM (deep-learning reference predictor); lipoproteins from a (myco)bacterial lipobox motif. A sequence-based prediction of subcellular context.

Physico-chemical properties (computed, ProtParam)

Length	140 aa
Molecular weight	14.9 kDa
Theoretical pI	8.82
GRAVY	0.355 (hydrophobic)
Aliphatic index	98.4
Aromaticity	0.093
Instability index	39.4 (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
`CN_hydrolase`	PF00795	n/a	–	CN_hydrolase

3D structure (interactive — Mol*/pdbe-molstar)

No experimental structure is deposited for this gene: showing the AlphaFold DB predicted model (mean pLDDT 94.6, very high), coloured by per-residue confidence (dark blue = very high, orange/red = low — treat low-confidence regions as unreliable, especially termini and loops). Drag to rotate, scroll to zoom.

Structural search (AlphaFold DB model, Foldseek vs PDB — genome-wide) pLDDT 94.6

PDB hit	prob	TM (aln)	TM (query)	TM (target)	Seq. id.	Cov. q / t	E-value	Description
`8aq2-assembly1_A`	1.00	0.82	0.67	0.19	24%	78% / 21%	1.5e-05 sig	8aq2-assembly1_A In meso structure of the membrane integral lipoprotein N-acyltransferase Lnt from P. aeruginosa covalently linked with TITC
`5vrg-assembly1_A`	1.00	0.78	0.73	0.23	20%	91% / 26%	6.0e-05 sig	5vrg-assembly1_A Structural insights into lipoprotein N-acylation by Escherichia coli apolipoprotein N-acyltransferase
`5n6h-assembly1_A`	1.00	0.78	0.73	0.22	20%	91% / 25%	8.7e-05 sig	5n6h-assembly1_A Structure of the membrane integral lipoprotein N-acyltransferase Lnt from E. coli
`6nwr-assembly1_A`	1.00	0.78	0.72	0.23	20%	89% / 25%	7.7e-05 sig	6nwr-assembly1_A Thioester acyl-intermediate of Apolipoprotein N-acyltransferase (Lnt)
`7aci-assembly1_A`	1.00	0.78	0.73	0.22	20%	91% / 25%	9.3e-05 sig	7aci-assembly1_A In meso structure of apolipoprotein N-acyltransferase, Lnt, from Escherichia coli in 9.8 monoacylglycerol

Foldseek search of the AlphaFold DB model (mean pLDDT 94.6, 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.

Functional interaction network (STRING v12, guilt-by-association)

Explore full network →

Node colour = verdict, dashed = still uncharacterised; 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: Rv2262c (Conserved hypothetical protein; Catalyzes the phospholipid dependent N-acylation of the N- terminal cysteine of apolipoprotein, the last ste), high confidence (score 991, all STRING channels except text-mining; the partner is chosen on its genomic-context evidence).

All 12 partner(s) at medium confidence are shown. None rests on an interaction measured in M. tuberculosis itself.

Partner	Product	Score	No text-mining	Channels (≥400)
`Rv2262c`	Conserved hypothetical protein; Catalyzes the phospholipid dependent N-acylation of the N- terminal cysteine of apolipoprotein, the last ste	991	991 ctx	neighborhood:773 fusion:891 cooccurence:571
`Rv2263`	oxidoreductase	554	555 ctx	neighborhood:553
`Rv2209`	integral membrane protein	460	440 ctx	cooccurence:431
`Rv2819c` csm5	CRISPR type III-associated RAMP protein Csm5	424	425 ctx	cooccurence:421
`Rv2337c`	hypothetical protein	424	424 ctx	cooccurence:412
`Rv0355c` PPE8	PPE family protein PPE8	404	404
`Rv2490c` PE_PGRS43	PE-PGRS family protein PE_PGRS43	404	404 ctx	cooccurence:404
`Rv0842`	integral membrane protein	404	382
`Rv1004c`	membrane protein	414	380
`Rv1539` lspA	lipoprotein signal peptidase	933	76	textmining:931
`Rv1614` lgt	prolipoprotein diacylglyceryl transferase	506	73	textmining:489
`Rv3623` lpqG	lipoprotein LpqG	876	44	textmining:876

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 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.

Where the experimental evidence comes from, and why it matters here. STRING's experimental channel fuses interactions measured in M. tuberculosis with interactions measured in another organism and transferred to this pair by orthology. The two are not equivalent for this atlas, whose standing rule is that better studied elsewhere is not a function established in M. tuberculosis. Measured on the served network: of the 38 229 partner pairs shown across the atlas, 13 483 partner rows carry a non-zero experimental channel, and only 106 pairs rest on an interaction measured in M. tuberculosis itself — 0.3 % of the network. Those 106 are long-established complexes (ESX-1/ESAT-6, RNA polymerase with CarD and RbpA, the Pup–Mpa proteasome, gyrase, Emb, GarA with PknB and PknG, the Rel modules); no still-uncharacterised gene is among them. The reason is not a gap in this atlas but in the literature: there is almost no experimental interactome of this bacterium, IntAct holding 134 curated protein pairs for a ~4 000-gene proteome. A exp (transferred) badge is therefore a lead, never a measurement, and an absence of badge is not evidence that the pair does not interact.

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 )
Domains: Pfam-A via hmmscan --cut_ga — CN_hydrolase (PF00795)
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 COG0815
Curated reference: UniProt I6XDW5 (TrEMBL, unreviewed)
Intra-MTBC selection: pN/pS and disruption from SPDI variants of 142 601 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 94.6)
Interaction network: STRING v12.0 (Szklarczyk et al. 2023, doi:10.1093/nar/gkac1000), taxon 83332, CC-BY 4.0 — 12 functional partner(s); context anchor Rv2262c
Essentiality: genome-wide transposon mutagenesis in H37Rv — DeJesus et al. 2017 (mBio, doi:10.1128/mBio.02133-16, CC BY)
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)
Physico-chemical properties: ExPASy ProtParam method via Biopython (Gasteiger et al. 2005), computed from the MTBC0 sequence
Predicted localisation: DeepTMHMM (Hallgren et al. 2022, doi:10.1101/2022.04.08.487609) for transmembrane topology and signal peptide
Primary literature: none located yet; annotation rests on the domain/homology sources above.

Ancestral MTBC0 protein sequence

>|Rv2261c|Rv2261c
LHIAPLISYEMTFSDLTRHAARLGAALLVYQSSTSTFQGSWAQPQLAAQPAVRAVEAGIPAVHASLSGDSSAFDTRGRRLAWCSAEFNGAIVVNVPLASNVTLYLRLGDWVPVTAFVVMGAGFAVFLRRSLARVSDCADK

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