Affinage · Plasmodium

RAB6

PF3D7_1144900 · ras-related protein Rab-6

Annotated
2026-09-08
16 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAB6 (PF3D7_1144900) is a Ras-like GTPase of Plasmodium falciparum that serves as a marker and regulator of the trans-Golgi compartment during the intraerythrocytic cycle (PMID:9010846, PMID:18284574). Immunofluorescence and immunoelectron microscopy place RAB6 in 4–7 discrete, tubulovesicular foci that are spatially distinct from the cis-Golgi/early-Golgi markers PfERD2 and PfGRASP, establishing that the parasite Golgi is dispersed and 'unstacked' rather than a single stacked stack, with RAB6 defining its trans face (PMID:9010846, PMID:17428488). Its GDP-bound nucleotide-binding domain crystallizes at 2.3 Å and adopts the classical Rab GTP/GDP switch architecture, but lacks the CDR features that mediate Rabkinesin-type effector binding in higher eukaryotes (PMID:10944329). RAB6-marked membranes behave as a functional Golgi compartment: they co-localize with Golgi-resident enzymes, redistribute into the ER upon brefeldin A treatment, and multiply in concert with the transitional ER during parasite maturation and schizogony (PMID:16704982, PMID:12165385, PMID:18284574). Beyond this trafficking-marker role, the effectors, GEFs/GAPs, and cargo of RAB6 have not been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 1996 Medium

    Establishing where RAB6 resides answered whether the parasite Golgi is organized like a canonical stacked Golgi, showing instead a dispersed trans-Golgi compartment distinct from early-Golgi markers.

    Evidence High-resolution immunofluorescence and immunoelectron microscopy against PfRab6 versus PfERD2 in P. falciparum, plus mRNA expression staging

    PMID:8885224 PMID:9010846 PMID:9237367

    Open questions at the time
    • Antibody-based localization does not identify RAB6 effectors or cargo
    • Function in trafficking inferred by analogy, not tested by perturbation
  2. 2000 High

    Solving the GDP-bound structure answered whether RAB6 uses the conserved Rab switch mechanism and whether it retains effector-binding features, revealing a classical switch but an absence of Rabkinesin-type CDR contacts.

    Evidence X-ray crystallography (MAD phasing, 2.3 Å) of recombinant PfRab6 nucleotide-binding domain expressed in E. coli, with a companion crystallization report

    PMID:10944329 PMID:10944341

    Open questions at the time
    • No GTP-bound structure to confirm the modeled switch transition
    • Predicted loss of Rabkinesin-6 binding not tested biochemically
    • No identified effector for the observed surface
  3. 2003 Low

    Modeling of the RabF/RabSF motifs addressed how putative interaction surfaces of RAB6 change with nucleotide state, supporting nucleotide-dependent remodeling of candidate effector-binding surfaces.

    Evidence Bioinformatic sequence analysis and structural/phylogenetic modeling of P. falciparum Rab family members

    PMID:12657463

    Open questions at the time
    • Computational only; no in vitro or cellular validation on RAB6
    • No effector identified for the modeled surfaces
  4. 2008 High

    Dual live imaging answered whether the RAB6-marked trans-Golgi is dynamically coupled to other secretory compartments, showing that its multiplication tracks transitional-ER multiplication during parasite maturation and links to cis/trans-Golgi spatial separation.

    Evidence Live fluorescence microscopy of double-transfectant P. falciparum expressing GRASP-GFP and RAB6-DsRed, plus multi-marker IFM and brefeldin A perturbation and Golgi-enzyme co-localization

    PMID:12165385 PMID:16704982 PMID:17428488 PMID:18284574

    Open questions at the time
    • Does not define the trafficking steps RAB6 catalyzes
    • GTPase cycling in vivo not linked to specific transport events
    • No loss-of-function phenotype reported
  5. 2022 Low

    A gametocyte interaction screen addressed whether RAB6 participates in stage-specific signaling, placing it among interactors of the receptor GPR180 in the cGMP-PKG-Ca2+ gametogenesis cascade in P. berghei.

    Evidence Affinity-based pulldown/co-IP in activated P. berghei gametocytes identifying RAB6 as a GPR180-interacting protein

    PMID:35404079

    Open questions at the time
    • Single interaction among several listed; no reciprocal validation
    • Interaction method not detailed in abstract
    • Functional consequence for RAB6 in gametogenesis untested
  6. 2024 Low

    Chemical target fishing addressed whether RAB6 is a druggable antiplasmodial target, identifying it as a candidate binder of a trichloromethylquinazoline compound.

    Evidence Affinity chromatography with immobilized compound applied to P. falciparum lysate

    PMID:38452406

    Open questions at the time
    • No confirmation of direct binding
    • No demonstrated inhibition of RAB6 GTPase activity or function

Open questions

Synthesis pass · forward-looking unresolved questions
  • The effectors, GEFs, GAPs, and specific cargo that RAB6 acts upon in the parasite trans-Golgi remain undefined, as does its requirement for parasite viability.
  • No effector or regulator (GEF/GAP) identified
  • No genetic loss-of-function phenotype
  • GTP-bound structure and in vivo nucleotide cycling not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
GPR180 (IN P. BERGHEI GAMETOCYTES) [#10]

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 RAB6 (PfRab6) protein localizes to 4–7 distinct foci in ring-stage parasites by high-resolution fluorescence microscopy, separate from the cis-Golgi marker PfERD2, indicating that early and late Golgi markers can be segregated and that Golgi membranes in P. falciparum rings are 'unstacked' tubulovesicular clusters. Immunoelectron microscopy showed both PfERD2 and PfRab6 membranes are tubulovesicular, devoid of cisternal morphology. High-resolution immunofluorescence microscopy and immunoelectron microscopy with antibodies specific to PfRab6 and PfERD2 in transgenic and native parasites Molecular and biochemical parasitology Medium 9010846
1996 RAB6 (PfRab6) mRNA is expressed throughout the intraerythrocytic cycle with maximal expression at the trophozoite stage; the protein redistributes during late schizogony, coalescing into multiple foci each associated with the nucleus of a forming daughter parasite. Immunofluorescence microscopy with specific antisera; mRNA expression analysis across intraerythrocytic cycle stages Molecular and biochemical parasitology Medium 8885224
1996 RAB6-related protein in P. falciparum localizes to the Golgi/trans-Golgi network by immunogold electron microscopy on ultrathin frozen sections, consistent with a role in vesicular trafficking analogous to its mammalian counterpart. Immunogold electron microscopy on ultrathin frozen sections of infected red blood cells Biology of the cell Medium 9237367
2000 The nucleotide-binding domain of RAB6 (PfRab6) was crystallized with GDP bound to the active site and its structure determined to 2.3 Å resolution by MAD phasing. Structural comparison with Rab3A (GTP and GDP forms) supports the classical GTP/GDP switch mechanism. A notable structural difference is the apparent lack of CDR (complementarity-determining region) features that mediate Rabkinesin-type effector binding in higher eukaryotes, suggesting RAB6 may not interact with Rabkinesin-6 homologs. X-ray crystallography (MAD phasing, 2.3 Å resolution) of recombinant PfRab6 nucleotide-binding domain expressed in E. coli Acta crystallographica. Section D, Biological crystallography High 10944329
2000 Full-length RAB6 (PfRab6, 208 amino acids) and a truncated form (residues 1–175) were successfully expressed in E. coli, purified, and crystallized; crystals diffracted to 2.4 Å (full-length) and 2.2 Å (truncated), establishing that recombinant PfRab6 protein can be produced in soluble, crystallizable form. Recombinant protein expression in E. coli, ion-exchange and size-exclusion chromatography purification, hanging-drop vapor-diffusion crystallization Acta crystallographica. Section D, Biological crystallography Low 10944341
2003 Structural modeling of PfRab6 with conserved RabF and RabSF motifs shows that their predicted positions on the structure change as GTP is hydrolyzed to GDP, supporting involvement in potential interaction surfaces analogous to those mediating Rabkinesin-6 binding on human Rab6. Bioinformatic sequence analysis, structure modeling, and phylogenetic comparison of Plasmodium falciparum Rab family members Gene Low 12657463
2006 Complete co-localization of phosphoethanolamine methyltransferase (Pfpmt) with RAB6 (used as a Golgi marker) in transgenic parasites expressing GFP-targeted constructs demonstrates that RAB6 marks the Golgi apparatus compartment in P. falciparum, and that the transmethylation step of phosphatidylcholine synthesis occurs there. Confocal microscopy co-localization of Pfpmt and GFP-targeted RAB6 in transgenic parasites The Journal of biological chemistry Medium 16704982
2007 RAB6 (PfRab6) compartments are spatially separate from PfGRASP (cis-Golgi marker) and PfBet3p compartments in transgenic parasites, confirming that RAB6 marks the trans-Golgi and that the Golgi is dispersed (not a single stacked structure) in P. falciparum. Immunofluorescence microscopy of transgenic parasites expressing chimeric fluorescent proteins for multiple Golgi/ER markers International journal for parasitology Medium 17428488
2008 In a double-transfectant parasite line expressing GRASP-GFP (cis-Golgi) and RAB6-DsRed (trans-Golgi), live imaging demonstrated spatial separation of cis- and trans-Golgi faces and showed that Golgi multiplication is closely linked to transitional ER multiplication during parasite maturation. Live fluorescence microscopy of double-transfectant P. falciparum parasites expressing GRASP-GFP and RAB6-DsRed fusion proteins Molecular microbiology High 18284574
2002 RAB6 (PfRab6) is located within the parasite and partly overlaps with the trans-Golgi region; treatment with brefeldin A causes a more complete overlap between delta-COP and the ER marker PfERC, with the Golgi (RAB6-marked) compartment redistributing into the ER, indicating that RAB6-marked membranes are sensitive to brefeldin A-induced Golgi disruption. Confocal immunofluorescence microscopy using affinity-purified antibodies against Pfdelta-COP and co-staining with PfRab6 and PfERC markers; brefeldin A treatment experiments Molecular and biochemical parasitology Medium 12165385
2022 In P. berghei activated gametocytes, RAB6 (small GTPase) was identified as an interaction partner of GPR180 (G-protein-coupled receptor 180) by co-immunoprecipitation or affinity-based proteomic approach, placing RAB6 in the context of the cGMP-PKG-Ca2+ gametogenesis signaling cascade. Protein-protein interaction study (affinity-based pulldown/co-IP) in activated P. berghei gametocytes identifying RAB6 as a GPR180-interacting protein Microbiology spectrum Low 35404079
2024 RAB6 (PfRab6 GTPase) was identified as a potential target of an antiplasmodial 4-anilino-2-trichloromethylquinazoline compound (Hit A) by affinity chromatography on plasmodial lysate using the compound immobilized on a solid support. Affinity chromatography (target fishing) using compound immobilized on solid support with PEG-type linkers applied to P. falciparum lysate Bioorganic & medicinal chemistry Low 38452406

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 The Plasmodium falciparum family of Rab GTPases. Gene 74 12657463
1996 Identification and localization of rab6, separation of rab6 from ERD2 and implications for an 'unstacked' Golgi, in Plasmodium falciparum. Molecular and biochemical parasitology 66 9010846
1996 Identification of a family of Rab G-proteins in Plasmodium falciparum and a detailed characterisation of pfrab6. Molecular and biochemical parasitology 64 8885224
1997 Rab GTPases and the unusual secretory pathway of plasmodium. Parasitology today (Personal ed.) 47 15275124
2008 Spatial dissection of the cis- and trans-Golgi compartments in the malaria parasite Plasmodium falciparum. Molecular microbiology 38 18284574
2007 Re-assessing the locations of components of the classical vesicle-mediated trafficking machinery in transfected Plasmodium falciparum. International journal for parasitology 34 17428488
2006 Localization of the phosphoethanolamine methyltransferase of the human malaria parasite Plasmodium falciparum to the Golgi apparatus. The Journal of biological chemistry 31 16704982
2002 Characterisation of a delta-COP homologue in the malaria parasite, Plasmodium falciparum. Molecular and biochemical parasitology 29 12165385
2000 Structure of the nucleotide-binding domain of Plasmodium falciparum rab6 in the GDP-bound form. Acta crystallographica. Section D, Biological crystallography 29 10944329
2022 A G-Protein-Coupled Receptor Modulates Gametogenesis via PKG-Mediated Signaling Cascade in Plasmodium berghei. Microbiology spectrum 15 35404079
1996 Small GTP-binding proteins in Plasmodium falciparum. Biology of the cell 12 9237367
2005 [Protein traffic in Plasmodium infected-red blood cells]. Medecine sciences : M/S 8 15885204
1998 An amino terminal intron indicates that transcripts for the Plasmodium falciparum Golgi network marker Rab6 do not encode alternative amino termini. Molecular and biochemical parasitology 6 9719520
2000 Plasmodium falciparum rab6 GTPase: expression, purification, crystallization and preliminary crystallographic studies. Acta crystallographica. Section D, Biological crystallography 1 10944341
1999 Gene organization of rab6, a marker for the novel Golgi of Plasmodium. Molecular and biochemical parasitology 1 10391383
2024 Target fishing reveals PfPYK-1 and PfRab6 as potential targets of an antiplasmodial 4-anilino-2-trichloromethylquinazoline hit compound. Bioorganic & medicinal chemistry 0 38452406