Curation Notes for Variovorax paradoxus czcA3 (A0A0H2MBF7, VPARA_44890)

Overview

• UniProt Accession: A0A0H2MBF7 (A0A0H2MBF7_VARPD)
• Ordered Locus Name: VPARA_44890
• Gene Symbol: czcA3
• Organism: Variovorax paradoxus (NCBITaxon:34073, strain TBEA6; for species-level context in the sequenced strain S110 genome announcement, see PMID:21183664)
• Protein Function: Predicted inner-membrane proton/cation antiporter subunit (CzcA3, 1,067 aa) of a heavy-metal efflux resistance-nodulation-division (HME-RND) tripartite efflux pump (CzcCBA), which couples the proton-motive force across the cytoplasmic membrane to the active extrusion of monoatomic divalent metal cations.
• Prospective Hypothesis on Substrate Specificity: While NCBIfam:TIGR00914 (heavy metal efflux pump, CzcA family) and InterPro:IPR004763 (CusA/CzcA subfamily) strongly support inorganic divalent metal cation efflux ($\text{Co}^{2+}$, $\text{Zn}^{2+}$, $\text{Cd}^{2+}$) by homology to Cupriavidus metallidurans CzcA, the exact metal substrate profile of VPARA_44890 (czcA3) among the multiple CzcA paralogs in V. paradoxus remains a prospective hypothesis awaiting $\Delta czcA3$ mutant metal-MIC profiling.

Domain Architecture & Subfamily Classification (UniProtKB:A0A0H2MBF7)

1. 12-Transmembrane HME-RND Pump Topology:
2. Contains 12 transmembrane $\alpha$-helices (FT TRANSMEM) and large periplasmic pore/TolC-docking loops (Pfam:PF00873 ACR_tran, InterPro:IPR001036, InterPro:IPR027463).
3. Specific Membership in the Heavy-Metal Efflux (HME-RND) CusA/CzcA Subfamily (InterPro:IPR004763, NCBIfam:TIGR00914):
4. Crucially, A0A0H2MBF7 matches NCBIfam:TIGR00914 (2A0601: heavy metal efflux pump, CzcA family) and InterPro:IPR004763 (Efflux pump, RND family, CusA/CzcA subfamily), distinguishing it from hydrophobe/amphiphile (HAE-RND, AcrB/MexB) multidrug/xenobiotic efflux pumps.

Review of Existing GOA Annotations

• GO:0005886 (plasma membrane, IEA via TreeGrafter PTN002424683 and UniProtKB-SubCell) -> ACCEPT (integral inner-membrane RND transporter with 12 TM helices).
• GO:0016020 (membrane, IEA via InterPro / UniProtKB-KW) -> TOO_GENERAL (subsumed by the accepted child term GO:0005886 plasma membrane on this record).
• GO:0008324 (monoatomic cation transmembrane transporter activity, IEA via InterPro IPR004763) -> ACCEPT (transports divalent metal cations across the inner membrane).
• GO:0022857 (transmembrane transporter activity, IEA via InterPro IPR001036) -> TOO_GENERAL (subsumed by the accepted child term GO:0008324 monoatomic cation transmembrane transporter activity on this record).
• GO:0098655 (monoatomic cation transmembrane transport, IEA via InterPro IPR004763) -> ACCEPT (core biological process).
• GO:0006812 (monoatomic cation transport, IEA via GOC-owl) -> TOO_GENERAL (subsumed by the accepted child term GO:0098655 monoatomic cation transmembrane transport on this record).
• GO:0055085 (transmembrane transport, IEA via InterPro IPR001036) -> TOO_GENERAL (subsumed by the accepted child term GO:0098655 monoatomic cation transmembrane transport on this record).
• GO:0042910 (xenobiotic transmembrane transporter activity, IEA via TreeGrafter PTN002424683) -> REMOVE (TreeGrafter over-propagation from HAE-RND multidrug efflux paralogs; CzcA3 belongs to the HME-RND TIGR00914 / IPR004763 metal cation efflux subfamily).
• GO:0042908 (xenobiotic transport, IEA via GOC-owl from GO:0042910) -> REMOVE.