Rv1804c Resolved · medium
H37Rv Rv1804c · MTBC0 mtbc0_001917 ·
108 aa · 2065034–2065360 (-) ·
RefSeq NP_216320.1
Annotation: from legacy to revised
| Legacy (H37Rv / Mycobrowser) | hypothetical protein |
|---|---|
| MTBC0 PGAP re-annotation | DUF732 domain-containing protein |
| Revised (this work) | Secreted protein that activates macrophage pro-inflammatory responses by binding the host IkappaB-alpha PEST domain. RefSeq leaves it 'hypothetical'. Highly conserved secretory Rv1804c directly interacts with the PEST domain of IkappaB-alpha, activating it in an IKKalpha-independent manner; it inhibits mycobacterial survival and is enriched in attenuated rather than virulent strains (Zheng 2024). Also an antibody-eliciting antigen in active TB (Ben Amor 2005). |
Curated reference (UniProt)
| UniProt |
O53953
TrEMBL · unreviewed
· Predicted
|
|---|---|
| UniProt name | Conserved protein |
UniProt still lists this protein as Conserved protein; the revised annotation above is ahead of the current UniProt record.
Functional vocabulary (eggNOG-mapper, orthology transfer)
| COG category |
S Function unknown
|
|---|---|
| eggNOG description | Protein of unknown function (DUF732) |
| Orthologous group | 2B16Q |
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, 2 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)
| Pfam | Accession | i-Evalue | Residues | Description |
|---|---|---|---|---|
DUF732 | PF05305.20 | 1.0e-17 | 27–97 | Protein of unknown function (DUF732) |
Structural neighbours (Foldseek on the ESMFold model, exploratory)
ESMFold model confidence: mean pLDDT 71.5 (confident). A confident model makes the fold comparison meaningful.
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 |
|---|---|---|---|---|
3lcn-assembly2_B |
0.21 | 0.48 | 2.4e+00 | 3lcn-assembly2_B Nab2:Gfd1 complex |
2gtg-assembly1_A |
0.14 | 0.44 | 3.2e+00 | 2gtg-assembly1_A Crystal Structure of Human Saposin C |
4a8e-assembly1_A-2 |
0.10 | 0.43 | 6.1e+00 | 4a8e-assembly1_A-2 The structure of a dimeric Xer recombinase from archaea |
2k48-assembly1_A |
0.03 | 0.22 | 6.8e+00 | 2k48-assembly1_A NMR Structure of the N-terminal Coiled Coil Domain of the Andes Hantavirus Nucleocapsid Protein |
Functional interaction network (STRING v12, guilt-by-association)
Closest characterised functional partner: PE_PGRS32 (PE-PGRS family protein PE_PGRS32), medium confidence from genomic context alone (score 461 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) |
|---|---|---|---|---|
Rv1803c PE_PGRS32 |
PE-PGRS family protein PE_PGRS32 | 460 | 461 ctx | neighborhood:461 |
Rv1805c hyp |
hypothetical protein | 418 | 419 ctx | neighborhood:415 |
Rv0603 hyp |
hypothetical protein | 871 | 53 | textmining:870 |
Rv2253 hyp |
hypothetical protein | 870 | 47 | textmining:870 |
Rv0203 hyp |
hypothetical protein | 696 | 41 | textmining:696 |
Rv0934 pstS1 |
phosphate ABC transporter substrate-binding lipoprotein PstS | 511 | 41 | textmining:511 |
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
- Secreted; binds IkappaB-alpha PEST domain, activates pro-inflammatory response (Zheng 2024, PMID 38384838)
- Antibody-eliciting secreted antigen (Ben Amor 2005, PMID 15683450)
- 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_216320.1)
- Domains: Pfam-A via hmmscan --cut_ga — DUF732 (PF05305.20)
- 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
2B16Q - Curated reference: UniProt O53953 (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 71.5, confident)
- Interaction network: STRING v12.0 (Szklarczyk et al. 2023,
doi:10.1093/nar/gkac1000), taxon 83332, CC-BY 4.0 —
6 functional partner(s); context anchor
PE_PGRS32 - Primary literature: Zheng J, Dong C, Xiong S (2024). Mycobacterial Rv1804c binds to the PEST domain of IkappaBalpha and activates macrophage-mediated proinflammatory responses iScience 27(3):109101. doi:10.1016/j.isci.2024.109101 PMID:38384838
Ancestral MTBC0 protein sequence
>mtbc0_001917|Rv1804c| MRVVSTLLSIPLMIGLAVPAHAGPSGDDAVFLASLERAGITYSHPDQAIASGKAVCALVESGESGLQVVNELRTRNPGFSMDGCCKFAAISAHVYCPHQITKTSVSAK