Rv3354 Resolved · high
H37Rv Rv3354 · MTBC0 mtbc0_003569 ·
129 aa · 3795819–3796208 (+) ·
RefSeq NP_217871.1
Annotation: from legacy to revised
| Legacy (H37Rv / Mycobrowser) | hypothetical protein |
|---|---|
| MTBC0 PGAP re-annotation | DUF732 domain-containing protein |
| Revised (this work) | Secreted protein kinase effector that targets the host COP9 signalosome to suppress apoptosis. RefSeq leaves it 'hypothetical'. Rv3354 is secreted into mononuclear phagocytes and is required for virulence; it targets the JAMM metalloprotease domain of COP9-signalosome subunit 5 (CSN5), destabilising cullin-RING ubiquitin-ligase activity and suppressing apoptosis (Danelishvili 2014). A secreted protein with a signal sequence conserved in M. leprae. |
Curated reference (UniProt)
| UniProt |
O50383
TrEMBL · unreviewed
· Evidence at protein level
|
|---|---|
| UniProt name | DUF732 domain-containing protein |
Functional vocabulary (eggNOG-mapper, orthology transfer)
| COG category |
S Function unknown
|
|---|---|
| eggNOG description | Protein of unknown function (DUF732) |
| Orthologous group | 2EPYI |
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 | 0.715 · relaxed/neutral |
|---|---|
| Polymorphic sites (≥ 0.1% of strains) | 1 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 | 1.7e-15 | 36–107 | Protein of unknown function (DUF732) |
Structural neighbours (Foldseek on the ESMFold model, exploratory)
ESMFold model confidence: mean pLDDT 69.6 (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 |
|---|---|---|---|---|
2jps-assembly1_A |
0.12 | 0.50 | 7.6e+00 | 2jps-assembly1_A NAB2 N-terminal domain |
1xl3-assembly2_B |
0.07 | 0.45 | 8.9e+00 | 1xl3-assembly2_B Complex structure of Y.pestis virulence Factors YopN and TyeA |
7zx7-assembly1_M |
0.05 | 0.29 | 6.1e+00 | 7zx7-assembly1_M Structure of SNAPc containing Pol II pre-initiation complex bound to U1 snRNA promoter (CC) |
Functional interaction network (STRING v12, guilt-by-association)
Closest characterised functional partner: Rv3352c (oxidoreductase), medium confidence from genomic context alone (score 421 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) |
|---|---|---|---|---|
Rv3103c hyp |
hypothetical protein | 875 | 837 | experimental:814 |
Rv0397 hyp |
hypothetical protein | 694 | 675 | experimental:470 |
Rv1945 hyp |
hypothetical protein | 693 | 674 | experimental:470 |
Rv0297 PE_PGRS5 |
PE-PGRS family protein PE_PGRS5 | 693 | 674 | experimental:470 |
Rv1702c hyp |
hypothetical protein | 693 | 674 | experimental:470 |
Rv0393 hyp |
hypothetical protein | 693 | 674 | experimental:470 |
Rv3653 PE_PGRS61 |
PE-PGRS family-related protein PE_PGRS61 | 693 | 674 | experimental:470 |
Rv2588c yajC |
membrane protein secretion factor YajC | 676 | 625 | experimental:625 |
Rv3353c hyp |
hypothetical protein | 592 | 592 ctx | neighborhood:589 |
Rv3352c |
oxidoreductase | 421 | 421 ctx | neighborhood:419 |
Rv3675 |
membrane protein | 526 | 70 | textmining:512 |
Rv2068c blaC |
beta-lactamase | 464 | 62 | textmining:453 |
Rv3654c hyp |
hypothetical protein | 411 | 42 | textmining:411 |
Rv3364c hyp |
hypothetical protein | 803 | 41 | textmining:803 |
Rv1934c fadE17 |
acyl-CoA dehydrogenase FadE17 | 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
- Encodes a protein kinase; secreted effector required for virulence (Danelishvili 2014, PMID 25139900)
- Targets COP9-signalosome CSN5 JAMM metalloprotease; suppresses macrophage apoptosis
- Secreted protein conserved with M. leprae signal sequence
- 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_217871.1)
- 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
2EPYI - Curated reference: UniProt O50383 (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 69.6, low)
- Interaction network: STRING v12.0 (Szklarczyk et al. 2023,
doi:10.1093/nar/gkac1000), taxon 83332, CC-BY 4.0 —
15 functional partner(s); context anchor
Rv3352c - Primary literature: Danelishvili L, Babrak L, Rose SJ, Everman J, Bermudez LE (2014). Mycobacterium tuberculosis alters the metalloprotease activity of the COP9 signalosome mBio 5(4):e01278-14. doi:10.1128/mBio.01278-14 PMID:25139900
Ancestral MTBC0 protein sequence
>mtbc0_003569|Rv3354| MNLRRHQTLTLRLLAASAGILSAAAFAAPAQANPVDDAFIAALNNAGVNYGDPVDAKALGQSVCPILAEPGGSFNTAVASVVARAQGMSQDMAQTFTSIAISMYCPSVMADVASGNLPALPDMPGLPGS