Rv2647 Resolved · high
H37Rv Rv2647 · MTBC0 - ·
154 aa · 2971563–2972027 (+) ·
RefSeq NP_217163.2
Annotation: from legacy to revised
| Legacy (H37Rv / Mycobrowser) | hypothetical protein |
|---|---|
| MTBC0 PGAP re-annotation | — |
| Revised (this work) | Secreted virulence factor that inhibits macrophage pyroptosis by promoting NLRP3 ubiquitination/degradation. RefSeq leaves it 'hypothetical'. Rv2647 binds ISG15 and competitively inhibits ISGylation of NLRP3, enhancing its ubiquitination and degradation; this inactivates NLRP3-caspase-1-GSDMD, reduces IL-1beta and promotes Mtb survival (Jin 2025). |
Annotated on the H37Rv protein: this gene has no 1:1 ancestral MTBC0 anchor (PE/PPE, paralogue, IS element, or otherwise unanchored CDS).
Curated reference (UniProt)
| UniProt |
I6YDZ2
TrEMBL · unreviewed
· Predicted
|
|---|---|
| UniProt name | Uncharacterized protein |
UniProt still lists this protein as Uncharacterized protein; the revised annotation above is ahead of the current UniProt record.
Functional vocabulary (eggNOG-mapper, orthology transfer)
| COG category |
K Transcription
|
|---|---|
| eggNOG description | chromosome segregation |
| Orthologous group | COG1475 |
| KEGG orthology |
K03497
|
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 | n/a |
|---|---|
| Polymorphic sites (≥ 0.1% of strains) | 0 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.
Domains (Pfam, hmmscan --cut_ga)
No Pfam-A domain above the gathering threshold (or not yet scanned).
Structural neighbours (Foldseek on the ESMFold model, exploratory)
ESMFold model confidence: mean pLDDT 64.6 (low). Low-confidence model: the fold may be unreliable, so treat these structural hits with caution.
Best matches against the PDB, ranked by Foldseek homology probability. A high probability / TM-score suggests a shared fold; unless flagged sig (E < 0.01) these are fold hypotheses, not assignments.
| Target | Prob | TM | E-value | Description |
|---|---|---|---|---|
5k5d-assembly1_A |
0.99 | 0.51 | 1.6e-02 | 5k5d-assembly1_A Structure of the C2221 form of Pnob8-like ParB-N domain |
1hq1-assembly1_A |
0.07 | 0.52 | 9.2e+00 | 1hq1-assembly1_A STRUCTURAL AND ENERGETIC ANALYSIS OF RNA RECOGNITION BY A UNIVERSALLY CONSERVED PROTEIN FROM THE SIGNAL RECOGNITION PARTICLE |
3gwk-assembly1_C |
0.03 | 0.32 | 7.1e+00 | 3gwk-assembly1_C Structure of the homodimeric WXG-100 family protein from Streptococcus agalactiae |
9fia-assembly1_B3 |
0.02 | 0.23 | 7.6e+00 | 9fia-assembly1_B3 SSU(body) structure derived from the SSU sample of the mitoribosome from T. gondii. |
Functional interaction network (STRING v12, guilt-by-association)
Closest characterised functional partner: Rv2646 (integrase), high confidence from genomic context alone (score 866 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) |
|---|---|---|---|---|
Rv2646 |
integrase | 872 | 866 ctx | neighborhood:520 coexpression:732 |
Rv3918c parA |
chromosome partitioning protein ParA | 693 | 674 | coexpression:484 |
Rv1708 |
initiation inhibitor protein | 690 | 671 | coexpression:479 |
Rv3213c |
SOJ/ParA-like protein | 686 | 666 | coexpression:471 |
Rv2645 hyp |
hypothetical protein | 553 | 553 ctx | neighborhood:529 |
Rv3919c gid |
16S rRNA (guanine(527)-N(7))-methyltransferase RsmG | 553 | 503 | coexpression:474 |
Rv2649 |
Rv2649, (MTCY441.18), len: 328 aa. Probable transposase for IS6110. Identical to many other M. tuberculosis IS6110 transposase subunits. The | 490 | 490 ctx | neighborhood:490 |
Rv2648 |
Rv2648, (MTCY441.17A), len: 108 aa. Putative Transposase for IS6110 (fragment). Identical to many other M. tuberculosis IS6110 transposase s | 490 | 490 ctx | neighborhood:490 |
Rv3571 kshB |
3-ketosteroid-9-alpha-hydroxylase reductase subunit | 408 | 408 | |
Rv3230c |
stearoyl-CoA 9-desaturase electron transfer protein | 407 | 408 | |
Rv3554 fdxB |
electron transfer protein FdxB | 421 | 406 | |
Rv2776c |
oxidoreductase | 404 | 405 | |
Rv2150c ftsZ |
cell division protein FtsZ | 465 | 393 |
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.
Evidence
- Binds ISG15; inhibits NLRP3 ISGylation -> enhanced ubiquitination/degradation (Jin 2025, PMID 41032685)
- Inactivates NLRP3/caspase-1/GSDMD pyroptosis; promotes intracellular survival
- Curated from the literature crible (project 'Still unknown gene function', 2026-06-09)
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_217163.2)
- Domains: Pfam-A via hmmscan --cut_ga — none above threshold
- 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
COG1475 - Curated reference: UniProt I6YDZ2 (TrEMBL, unreviewed; Predicted)
- Intra-MTBC selection: pN/pS and disruption from SPDI variants of 145 209 MTBC strains (this work, local collection vs H37Rv NC_000962.3)
- Model confidence: ESMFold per-residue pLDDT (mean 64.6, low)
- Interaction network: STRING v12.0 (Szklarczyk et al. 2023,
doi:10.1093/nar/gkac1000), taxon 83332, CC-BY 4.0 —
13 functional partner(s); context anchor
Rv2646 - Primary literature: Jin X, Yan H, Chen X, Feng J, Li G, Yao J, Du X, Feng G (2025). Rv2647-Mediated NLRP3 Ubiquitination Inhibits Macrophage Pyroptosis and Promotes Mycobacterium tuberculosis Survival ACS Infect Dis 11(10):2739-2753. doi:10.1021/acsinfecdis.5c00192 PMID:41032685
Ancestral MTBC0 protein sequence
>H37Rv|Rv2647| MLQPIGVTPDRRLVFGQRRLEAARLLGWERIPVHVCHTIADVVDRAKAERSENTLRKDFTPSELLAAGRRIAELERPKAKQRQREGGDHGRQARYSGLGSMEPKPESERDAHKADTAISEALGISRGHYQRLKRIDNATRSEAGYRDGLNGWSG