Rv3033 Resolved · medium
H37Rv Rv3033 · MTBC0 mtbc0_003225 ·
182 aa · 3414690–3415238 (+) ·
RefSeq NP_217549.1
Annotation: from legacy to revised
| Legacy (H37Rv / Mycobrowser) | hypothetical protein |
|---|---|
| MTBC0 PGAP re-annotation | DUF4333 domain-containing protein |
| Revised (this work) | Secreted anti-apoptotic virulence factor. RefSeq leaves it 'hypothetical'. Rv3033 represses the intrinsic (caspase-9-mediated) but not the extrinsic apoptotic pathway in infected macrophages, blocking both mitochondrial cytochrome-c release and ER-stress (PERK) activation, thereby promoting bacillary survival (Zhang 2018). |
Curated reference (UniProt)
| UniProt |
I6YAY5
TrEMBL · unreviewed
· Evidence at protein level
|
|---|---|
| UniProt name | DUF4333 domain-containing protein |
Functional vocabulary (eggNOG-mapper, orthology transfer)
| COG category |
S Function unknown
|
|---|---|
| eggNOG description | Domain of unknown function (DUF4333) |
| Orthologous group | 2E9A0 |
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 | 0.633 · relaxed/neutral |
|---|---|
| Polymorphic sites (≥ 0.1% of strains) | 1 synonymous, 2 missense, 0 nonsense, 1 frameshift |
| Disruption | 1 distinct premature-stop/frameshift site(s); most common in 0.63% of strains (914) · clonal |
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 |
|---|---|---|---|---|
DUF4333 | PF14230.12 | 2.6e-22 | 23–97 | Domain of unknown function (DUF4333) |
Structural neighbours (Foldseek on the ESMFold model, exploratory)
ESMFold model confidence: mean pLDDT 91.5 (very high). 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 |
|---|---|---|---|---|
4lmi-assembly1_A |
0.60 | 0.63 | 1.6e+00 | 4lmi-assembly1_A Crystal structure of putative ketosteroid isomerase from Kribbella flavida DSM 17836 |
6w3w-assembly1_A |
0.51 | 0.60 | 1.8e+00 | 6w3w-assembly1_A An enumerative algorithm for de novo design of proteins with diverse pocket structures |
4r80-assembly2_B |
0.33 | 0.51 | 2.0e+00 | 4r80-assembly2_B Crystal Structure of a De Novo Designed Beta Sheet Protein, Cystatin Fold, Northeast Structural Genomics Consortium (NESG) Target OR486 |
8bl9-assembly1_A |
0.30 | 0.55 | 2.7e+00 | 8bl9-assembly1_A Crystal Structure of Sam0.7 |
5trv-assembly1_A |
0.30 | 0.50 | 2.0e+00 | 5trv-assembly1_A Crystal structure of a de novo designed protein with curved beta-sheet |
5tph-assembly1_A |
0.30 | 0.61 | 3.7e+00 | 5tph-assembly1_A Crystal structure of a de novo designed protein homodimer with curved beta-sheet |
3en8-assembly1_A-2 |
0.30 | 0.52 | 2.7e+00 | 3en8-assembly1_A-2 Crystal structure of NTF-2 like protein of unknown function (YP_553245.1) from BURKHOLDERIA XENOVORANS LB400 at 1.85 A resolution |
5l33-assembly1_A |
0.21 | 0.68 | 4.6e+00 | 5l33-assembly1_A Crystal structure of a de novo designed protein with curved beta-sheet |
Functional interaction network (STRING v12, guilt-by-association)
Closest characterised functional partner: Rv0479c (membrane protein), medium confidence from genomic context alone (score 591 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) |
|---|---|---|---|---|
Rv1006 hyp |
hypothetical protein | 765 | 765 ctx | cooccurence:764 |
Rv1868 hyp |
hypothetical protein | 761 | 761 ctx | cooccurence:760 |
Rv1435c hyp |
hypothetical protein | 745 | 745 ctx | cooccurence:745 |
Rv2047c hyp |
hypothetical protein | 698 | 698 ctx | cooccurence:698 |
Rv2598 hyp |
hypothetical protein | 688 | 688 ctx | cooccurence:685 |
Rv0210 hyp |
hypothetical protein | 631 | 631 ctx | cooccurence:631 |
Rv2114 hyp |
hypothetical protein | 626 | 626 ctx | cooccurence:624 |
Rv0479c |
membrane protein | 591 | 591 ctx | cooccurence:588 |
Rv3166c hyp |
hypothetical protein | 589 | 589 ctx | cooccurence:583 |
Rv0180c |
transmembrane protein | 563 | 563 ctx | cooccurence:563 |
Rv2597 |
membrane protein | 558 | 559 ctx | cooccurence:558 |
Rv3448 eccD4 |
ESX-4 secretion system protein EccD4 | 543 | 543 ctx | cooccurence:542 |
Rv1364c |
sigma factor regulatory protein | 510 | 511 ctx | cooccurence:508 |
Rv2560 hyp |
hypothetical protein | 497 | 498 ctx | cooccurence:496 |
Rv3450c eccB4 |
ESX-4 secretion system protein EccB4 | 493 | 493 ctx | cooccurence:490 |
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 virulence factor; represses intrinsic (caspase-9) apoptosis (Zhang 2018, PMID 30319611)
- Blocks mitochondrial cytochrome-c release and PERK ER-stress branch
- 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_217549.1)
- Domains: Pfam-A via hmmscan --cut_ga — DUF4333 (PF14230.12)
- 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
2E9A0 - Curated reference: UniProt I6YAY5 (TrEMBL, unreviewed; 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)
- Model confidence: ESMFold per-residue pLDDT (mean 91.5, very high)
- Interaction network: STRING v12.0 (Szklarczyk et al. 2023,
doi:10.1093/nar/gkac1000), taxon 83332, CC-BY 4.0 —
33 functional partner(s); context anchor
Rv0479c - Primary literature: Zhang W, Lu Q, Dong Y, Yue Y, Xiong S (2018). Rv3033, as an Emerging Anti-apoptosis Factor, Facilitates Mycobacteria Survival via Inhibiting Macrophage Intrinsic Apoptosis Front Immunol 9:2136. doi:10.3389/fimmu.2018.02136 PMID:30319611
Ancestral MTBC0 protein sequence
>mtbc0_003225|Rv3033| MAHSIVRTLLASGAATALIAIPTACSFSIGTSHSHSVSKAEVARQITAKMTDAAGNKPESVTCPSDLPAEVGAELNCEMKIKDRTFNVNVTVTSVDGSDVKFDMVETVDKNQVANIISDKLFQRVGARPDSVTCPDNLKGVEGAKLRCRLTDGSKTYGISVIVTSVDAGDVNFDFKVDDHPE