{"gene":"RABAC1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2003,"finding":"Yip3/PRA1 (RABAC1) acts catalytically as a GDI-displacement factor (GDF): it dissociates complexes of prenylated endosomal Rab GTPases (e.g., Rab9) bound to GDI and delivers them onto membranes. Purified Yip3/PRA1 protein reconstituted this GDF activity in vitro.","method":"Biochemical reconstitution with purified Yip3/PRA1 protein; in vitro GDF activity assay measuring Rab-GDI complex dissociation and membrane delivery","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified protein demonstrating catalytic GDF activity, replicated in a subsequent Methods in Enzymology paper (PMID:16473601)","pmids":["14574414","16473601"],"is_preprint":false},{"year":2000,"finding":"PRA1 (RABAC1) inhibits the extraction of membrane-bound Rab3A by GDI, opposing GDI-mediated Rab solubilization. PRA1 also binds weakly to GDI itself. Additionally, binding of Rab3A and VAMP2 to PRA1 is mutually exclusive: Rab3A can displace VAMP2 from a pre-formed VAMP2–PRA1 complex. The C-terminal domain of PRA1 is required for its soluble state; its deletion converts PRA1 into an integral membrane protein.","method":"Subcellular fractionation, immunocytochemistry, in vitro competition/binding assays, deletion mutagenesis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (fractionation, pulldown, mutagenesis) in a single lab study","pmids":["10751420"],"is_preprint":false},{"year":2001,"finding":"Mouse PRA1 (mPRA1) is a polytopic integral membrane protein with four transmembrane segments; all hydrophilic domains (N-terminus, inter-hydrophobic-domain linker, C-terminus) face the cytoplasm. The four TM segments act cooperatively during translocation/integration at the ER membrane.","method":"N-linked glycosylation scanning mutagenesis in intact cells and isolated microsomes; TM-segment substitution into a model membrane protein","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct topology mapping by glycosylation scanning and TM-substitution experiments, multiple orthogonal approaches in one study","pmids":["11535589"],"is_preprint":false},{"year":1999,"finding":"Human PRA1 (RABAC1) interacts with multiple Rab GTPases: strong interaction with Rab4b, Rab5a, and Rab5c; weak interaction with Rab4a, Rab6, Rab7, Rab17, and Rab22. The protein (~185 aa) is distributed between cytosol and membranes.","method":"Yeast two-hybrid screening of human brain cDNA library; Western blot of overexpressed protein after fractionation","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid only, single lab, no biochemical confirmation of direct binding","pmids":["10329441"],"is_preprint":false},{"year":2001,"finding":"PRA1 (RABAC1) interacts with EBV anti-apoptotic protein BHRF1 (a Bcl-2 homolog). Two PRA1 regions (aa 30–53 and C-terminal 21 residues) mediate BHRF1 binding; two BHRF1 regions (aa 1–18 and 89–142, containing BH4 and BH1 domains) are required. PRA1 expression reduces the anti-apoptotic activity of BHRF1 but not of Bcl-2.","method":"Yeast two-hybrid screen; GST pull-down assay; co-immunoprecipitation; confocal laser scanning microscopy; deletion/domain mapping mutagenesis; cell viability/apoptosis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, GST pulldown, and functional rescue in one study; single lab","pmids":["11373297"],"is_preprint":false},{"year":2006,"finding":"PRA1 (RABAC1) interacts with EBV oncoprotein LMP1 through LMP1's transmembrane domain, and colocalizes with LMP1 at the Golgi apparatus (colocalization sensitive to nocodazole and brefeldin A). PRA1 is required for proper intracellular trafficking of LMP1 and for LMP1-induced NF-κB activation; a PRA1 export mutant or PRA1 knockdown redistributes LMP1 to the ER and impairs NF-κB signaling, without affecting CD40- or TNFR1-mediated signaling or general Golgi integrity.","method":"Co-immunoprecipitation; immunofluorescence/confocal microscopy; nocodazole/brefeldin A treatment; PRA1 knockdown (RNAi); PRA1 export mutant overexpression; NF-κB luciferase reporter assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, knockdown with specific signaling readout, multiple orthogonal methods confirming Golgi-dependent trafficking role of PRA1 in LMP1 signaling","pmids":["16917502"],"is_preprint":false},{"year":2003,"finding":"Rotavirus spike protein VP4 interacts with PRA1 (RABAC1). A VP4 domain spanning aa 560–722 is essential for both PRA1 and Rab5 interactions; deletion/site-directed mutants of VP4 can selectively abolish binding to one partner. Interactions were confirmed in infected and transfected cells.","method":"Yeast two-hybrid screen; co-immunoprecipitation from infected/transfected cell lysates; site-directed and deletion mutagenesis of VP4","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP from both infected and transfected cells plus domain mapping; single lab","pmids":["12768023"],"is_preprint":false},{"year":2006,"finding":"PRA1 (RABAC1) binds β-catenin and inhibits TCF/β-catenin transcriptional signaling. PRA1 overexpression blocks nuclear translocation of β-catenin and reduces ERK1/2 phosphorylation. Deletion and site-directed PRA1 mutants and PRA1 siRNA confirmed these effects.","method":"Co-immunoprecipitation; confocal microscopy; TOPflash TCF luciferase reporter assay; site-directed and deletion mutagenesis; siRNA knockdown; nuclear fractionation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, reporter assay, mutagenesis, and knockdown converge on same conclusion; single lab","pmids":["16930546"],"is_preprint":false},{"year":2012,"finding":"NDRG2 (and other NDRG family members) binds PRA1 (RABAC1). NDRG2 and PRA1 co-expressed together synergistically downregulate TCF promoter activity and reduce GSK3β phosphorylation more than either protein alone.","method":"Yeast two-hybrid screen; GST pull-down; co-immunoprecipitation; confocal microscopy; TCF luciferase reporter assay; GSK3β phosphorylation immunoblot","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST pulldown + Co-IP + functional reporter assay, single lab","pmids":["23068607"],"is_preprint":false},{"year":2010,"finding":"PRA1 (RABAC1) depletion in NPC cells causes altered cell morphology, increased cell motility, and intracellular cholesterol accumulation. Proteins regulating lipid homeostasis and cell migration are upregulated upon PRA1 knockdown, and PRA1 overexpression can rescue dysregulation caused by either PRA1 knockdown or the cholesterol transport inhibitor U18666A. LMP1 expression sequesters PRA1 and phenocopies PRA1 knockdown effects on these proteins.","method":"Stable PRA1 knockdown cell clones; isobaric mass-tag labeling + multidimensional LC-MS proteomics; immunofluorescence staining; cholesterol staining; U18666A treatment; PRA1 overexpression rescue","journal":"Molecular & cellular proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with specific cellular phenotypes (motility, cholesterol), proteomics, and rescue experiment; single lab","pmids":["20592422"],"is_preprint":false},{"year":2019,"finding":"RABAC1/PRA1 binds the anti-apoptotic protein BCL2A1 and inhibits its anti-apoptotic function, inducing caspase-3 activation and apoptosis in AGS gastric cancer cells. RABAC1 also decreases cell proliferation, clonogenic survival, and cell migration/invasion.","method":"GST pull-down assay; co-immunoprecipitation; confocal microscopy; caspase-3 activity assay; clonogenic survival assay; cell migration/invasion assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST pulldown + Co-IP + functional apoptosis assays; single lab","pmids":["31003775"],"is_preprint":false},{"year":2020,"finding":"An endogenous subpopulation of PRA1 (RABAC1) resides at ER-mitochondria membrane contact sites. The cytosolic N-terminal region contains two ER retention/retrieval sequences: a membrane-distal di-arginine motif and a novel membrane-proximal FFAT-like motif. Mutation of either motif increases cell-surface localization; mutation of both has an additive effect. N- or C-terminal tagging of full-length PRA1 differentially redirects it to Golgi or reticular ER.","method":"Immunofluorescence and co-localization with ER/mitochondria markers in cultured mammalian cells; truncation and site-directed mutagenesis of retention motifs; flow cytometry for cell-surface expression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with mutagenesis establishing functional ER retention motifs; single lab, multiple orthogonal methods","pmids":["33259547"],"is_preprint":false},{"year":2024,"finding":"In yeast, Yip3 (ortholog of RABAC1/PRA1) is a target gene of the Ino2/Ino4 transcription factors and negatively regulates COPII-mediated vesicle transport from the ER. Yip3 acts by hindering Sec16 assembly on the ER membrane (distinct from Ino2/Ino4, which regulates Sar1 activation). This places Yip3 as a downstream effector in an ER lipid-sensing pathway that fine-tunes anterograde vesicular transport.","method":"Genetic epistasis in yeast (Ino2/Ino4 pathway); Sec16 assembly assay on ER membranes; Sar1 activation assay; transcriptional reporter analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic epistasis with defined molecular readouts (Sec16 assembly, Sar1 activation); preprint, single lab","pmids":[],"is_preprint":true}],"current_model":"RABAC1 (PRA1/Yip3) is a four-pass transmembrane protein localized predominantly to the Golgi apparatus, with subpopulations at ER-mitochondria contact sites, whose best-characterized function is to act as a catalytic GDI-displacement factor (GDF) that dissociates prenylated Rab–GDI complexes and delivers Rab GTPases onto target membranes; it also interacts with VAMP2 (in a manner mutually exclusive with Rab binding), β-catenin (inhibiting TCF/β-catenin signaling), the anti-apoptotic proteins BHRF1 and BCL2A1 (reducing their anti-apoptotic activity), and the EBV oncoprotein LMP1 (facilitating LMP1 Golgi trafficking and NF-κB signaling), and regulates lipid transport and cell migration downstream of Rab-trafficking homeostasis."},"narrative":{"mechanistic_narrative":"RABAC1 (PRA1/Yip3) is a polytopic, four-transmembrane integral membrane protein whose hydrophilic N-terminus, inter-domain linker, and C-terminus all face the cytoplasm [PMID:11535589], and whose best-characterized role is to control the membrane association of Rab GTPases during vesicular trafficking. Acting catalytically as a GDI-displacement factor (GDF), purified RABAC1 dissociates prenylated Rab–GDI complexes and delivers Rab GTPases onto target membranes [PMID:14574414, PMID:16473601]; it also opposes GDI-mediated extraction of membrane-bound Rab3A and binds Rab3A in a manner mutually exclusive with the SNARE VAMP2 [PMID:10751420]. Its subcellular distribution is governed by an N-terminal di-arginine motif and a membrane-proximal FFAT-like motif that retain a subpopulation at ER–mitochondria contact sites, with loss of these motifs redirecting the protein toward the cell surface [PMID:33259547]. Beyond Rab handling, RABAC1 serves as a trafficking adaptor and signaling modulator: it is required for Golgi trafficking of the EBV oncoprotein LMP1 and for LMP1-induced NF-κB activation [PMID:16917502], binds β-catenin to block its nuclear translocation and inhibit TCF/β-catenin transcription [PMID:16930546], and engages anti-apoptotic Bcl-2-family proteins BHRF1 and BCL2A1 to reduce their anti-apoptotic activity and promote caspase-3-dependent apoptosis [PMID:11373297, PMID:31003775]. Consistent with its trafficking role, RABAC1 depletion alters cell morphology, increases motility, and causes intracellular cholesterol accumulation [PMID:20592422].","teleology":[{"year":1999,"claim":"Establishing that RABAC1 physically engages multiple Rab GTPases defined it as a candidate Rab-pathway regulator rather than an isolated trafficking protein.","evidence":"Yeast two-hybrid screen of human brain cDNA plus fractionation of overexpressed protein","pmids":["10329441"],"confidence":"Low","gaps":["Yeast two-hybrid only, no biochemical confirmation of direct binding","Functional consequence of each Rab interaction not defined","Cytosol/membrane partitioning mechanism unresolved"]},{"year":2000,"claim":"Showing that PRA1 opposes GDI-mediated extraction of Rab3A and competes with VAMP2 reframed it as a regulator of the Rab membrane-cycling/SNARE interface.","evidence":"Subcellular fractionation, in vitro competition/binding assays, and deletion mutagenesis","pmids":["10751420"],"confidence":"Medium","gaps":["Whether GDI opposition reflects catalytic GDF activity not yet established here","Physiological significance of VAMP2 displacement untested in vivo","C-terminal control of solubility mechanistically unexplained"]},{"year":2001,"claim":"Mapping the membrane topology established the structural framework for how cytosolic domains can engage Rabs and binding partners.","evidence":"N-linked glycosylation scanning and TM-substitution mutagenesis in cells and microsomes","pmids":["11535589"],"confidence":"High","gaps":["No high-resolution structure","How cytosolic domains coordinate Rab vs partner binding unknown"]},{"year":2001,"claim":"Identifying BHRF1 binding and reduction of its anti-apoptotic activity linked RABAC1 to apoptotic control via viral Bcl-2 homologs.","evidence":"Yeast two-hybrid, GST pulldown, reciprocal Co-IP, domain mapping, and viability assays","pmids":["11373297"],"confidence":"Medium","gaps":["Mechanism by which binding lowers anti-apoptotic activity unclear","Selectivity for BHRF1 over Bcl-2 unexplained","Single lab"]},{"year":2003,"claim":"In vitro reconstitution with purified protein settled the central mechanistic question by demonstrating catalytic GDF activity that dissociates Rab–GDI complexes and delivers Rabs to membranes.","evidence":"Biochemical reconstitution with purified Yip3/PRA1 and an in vitro GDF assay","pmids":["14574414","16473601"],"confidence":"High","gaps":["Rab substrate specificity in cells not fully defined","Structural basis of GDI displacement unknown","Regulation of GDF activity in vivo unaddressed"]},{"year":2003,"claim":"Demonstrating rotavirus VP4 binding via a domain shared with Rab5 binding showed pathogens exploit the RABAC1 Rab interface during infection.","evidence":"Yeast two-hybrid plus Co-IP from infected and transfected cells with VP4 domain mapping","pmids":["12768023"],"confidence":"Medium","gaps":["Functional role in the viral life cycle not established","Whether VP4 and Rab5 compete for RABAC1 untested","Single lab"]},{"year":2006,"claim":"Defining RABAC1 as required for LMP1 Golgi trafficking and NF-κB activation revealed a trafficking-adaptor role coupling cargo localization to signaling output.","evidence":"Reciprocal Co-IP, confocal imaging with nocodazole/BFA, RNAi, export mutant, and NF-κB reporter assays","pmids":["16917502"],"confidence":"High","gaps":["Whether GDF/Rab activity is needed for LMP1 trafficking not separated","Generality to other Golgi-targeted cargo unknown"]},{"year":2006,"claim":"Showing β-catenin binding and inhibition of TCF signaling extended RABAC1's reach into Wnt-pathway transcriptional control.","evidence":"Co-IP, confocal microscopy, TOPflash reporter, mutagenesis, and siRNA with nuclear fractionation","pmids":["16930546"],"confidence":"Medium","gaps":["Mechanism blocking β-catenin nuclear entry undefined","Relationship to membrane/Rab function unclear","Single lab"]},{"year":2010,"claim":"Linking PRA1 depletion to increased motility and cholesterol accumulation connected its trafficking function to lipid homeostasis and migration phenotypes.","evidence":"Stable knockdown clones, quantitative LC-MS proteomics, cholesterol staining, and rescue experiments","pmids":["20592422"],"confidence":"Medium","gaps":["Direct molecular link from Rab/GDF activity to cholesterol transport unproven","Effector proteins driving migration not validated individually"]},{"year":2012,"claim":"Identifying NDRG2 as a partner that synergizes in downregulating TCF activity placed RABAC1 in a cooperative module of Wnt suppression.","evidence":"Yeast two-hybrid, GST pulldown, Co-IP, TCF reporter, and GSK3β phosphorylation immunoblot","pmids":["23068607"],"confidence":"Medium","gaps":["Biochemical basis of synergy with NDRG2 unknown","Connection to GSK3β regulation mechanistically unresolved"]},{"year":2019,"claim":"Showing BCL2A1 binding with induction of caspase-3 and reduced proliferation/invasion reinforced a pro-apoptotic, anti-tumor role through Bcl-2-family inhibition.","evidence":"GST pulldown, Co-IP, caspase-3 activity, clonogenic and migration/invasion assays in gastric cancer cells","pmids":["31003775"],"confidence":"Medium","gaps":["Mechanism of BCL2A1 inhibition undefined","In vivo tumor relevance not tested","Single lab"]},{"year":2020,"claim":"Identifying an ER–mitochondria contact-site pool and dual N-terminal retention motifs explained how RABAC1 steady-state localization is controlled.","evidence":"Co-localization with ER/mitochondria markers, retention-motif mutagenesis, and surface-expression flow cytometry","pmids":["33259547"],"confidence":"Medium","gaps":["Function at contact sites unknown","FFAT-like motif partner (e.g., VAP) not identified","Relationship of localization to GDF activity untested"]},{"year":2024,"claim":"Yeast Yip3 was shown to negatively regulate COPII transport by hindering Sec16 assembly, positioning the ortholog as an ER lipid-sensing effector of anterograde transport.","evidence":"Genetic epistasis in the Ino2/Ino4 pathway with Sec16 assembly and Sar1 activation assays (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, single lab, not peer-reviewed","Whether human RABAC1 regulates COPII similarly untested","Mechanism of Sec16 inhibition not at molecular detail"]},{"year":null,"claim":"How the catalytic GDF activity is mechanistically integrated with RABAC1's diverse non-Rab partners (β-catenin, Bcl-2 family, LMP1) and its contact-site localization remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of RABAC1 alone or with Rab/GDI","Unclear whether signaling roles depend on or are independent of GDF activity","Physiological Rab substrate repertoire in human cells undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,7]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[5]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,10]}],"complexes":[],"partners":["VAMP2","CTNNB1","BHRF1","BCL2A1","NDRG2","LMP1","RAB3A","RAB5A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UI14","full_name":"Prenylated Rab acceptor protein 1","aliases":["PRA1 family protein 1"],"length_aa":185,"mass_kda":20.6,"function":"General Rab protein regulator required for vesicle formation from the Golgi complex. May control vesicle docking and fusion by mediating the action of Rab GTPases to the SNARE complexes. In addition it inhibits the removal of Rab GTPases from the membrane by GDI","subcellular_location":"Cell membrane; Cytoplasm; Golgi apparatus; Cytoplasmic vesicle, secretory vesicle, synaptic vesicle","url":"https://www.uniprot.org/uniprotkb/Q9UI14/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RABAC1","classification":"Not Classified","n_dependent_lines":18,"n_total_lines":1208,"dependency_fraction":0.014900662251655629},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000105404","cell_line_id":"CID000444","localizations":[{"compartment":"golgi","grade":3},{"compartment":"vesicles","grade":3},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"ARL6IP1","stoichiometry":10.0},{"gene":"YIPF5","stoichiometry":10.0},{"gene":"MIF","stoichiometry":4.0},{"gene":"GOLT1B","stoichiometry":0.2},{"gene":"RAB1A","stoichiometry":0.2},{"gene":"RAB1B","stoichiometry":0.2},{"gene":"RAB2A","stoichiometry":0.2},{"gene":"RAB7A","stoichiometry":0.2},{"gene":"SFT2D3","stoichiometry":0.2},{"gene":"REEP5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000444","total_profiled":1310},"omim":[{"mim_id":"604925","title":"RAB ACCEPTOR 1; RABAC1","url":"https://www.omim.org/entry/604925"},{"mim_id":"300840","title":"PRA1 DOMAIN FAMILY, MEMBER 2; PRAF2","url":"https://www.omim.org/entry/300840"},{"mim_id":"185881","title":"VESICLE-ASSOCIATED MEMBRANE PROTEIN 2; VAMP2","url":"https://www.omim.org/entry/185881"},{"mim_id":"179508","title":"RAS-ASSOCIATED PROTEIN RAB1; RAB1","url":"https://www.omim.org/entry/179508"},{"mim_id":"179490","title":"RAS-ASSOCIATED PROTEIN RAB3A; RAB3A","url":"https://www.omim.org/entry/179490"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RABAC1"},"hgnc":{"alias_symbol":["PRA1","PRAF1","YIP3"],"prev_symbol":[]},"alphafold":{"accession":"Q9UI14","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UI14","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UI14-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UI14-F1-predicted_aligned_error_v6.png","plddt_mean":83.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RABAC1","jax_strain_url":"https://www.jax.org/strain/search?query=RABAC1"},"sequence":{"accession":"Q9UI14","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UI14.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UI14/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UI14"}},"corpus_meta":[{"pmid":"14574414","id":"PMC_14574414","title":"Yip3 catalyses the dissociation of endosomal Rab-GDI complexes.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/14574414","citation_count":208,"is_preprint":false},{"pmid":"22761575","id":"PMC_22761575","title":"Candida albicans scavenges host zinc via Pra1 during endothelial invasion.","date":"2012","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/22761575","citation_count":201,"is_preprint":false},{"pmid":"19850343","id":"PMC_19850343","title":"Immune evasion of the human pathogenic yeast Candida albicans: Pra1 is a Factor H, FHL-1 and plasminogen binding surface protein.","date":"2009","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19850343","citation_count":91,"is_preprint":false},{"pmid":"9440517","id":"PMC_9440517","title":"Cloning and characterization of PRA1, a gene encoding a novel pH-regulated antigen of Candida albicans.","date":"1998","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/9440517","citation_count":91,"is_preprint":false},{"pmid":"10751420","id":"PMC_10751420","title":"PRA1 inhibits the extraction of membrane-bound rab GTPase by GDI1.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10751420","citation_count":66,"is_preprint":false},{"pmid":"21565550","id":"PMC_21565550","title":"Immune escape of the human facultative pathogenic yeast Candida albicans: the many faces of the Candida Pra1 protein.","date":"2011","source":"International journal of medical microbiology : IJMM","url":"https://pubmed.ncbi.nlm.nih.gov/21565550","citation_count":55,"is_preprint":false},{"pmid":"10329441","id":"PMC_10329441","title":"Interaction cloning and characterization of the cDNA encoding the human prenylated rab acceptor (PRA1).","date":"1999","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10329441","citation_count":54,"is_preprint":false},{"pmid":"15221228","id":"PMC_15221228","title":"Isolation and characterization of PRA1, a trypsin-like protease from the biocontrol agent Trichoderma harzianum CECT 2413 displaying nematicidal activity.","date":"2004","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/15221228","citation_count":53,"is_preprint":false},{"pmid":"18625733","id":"PMC_18625733","title":"Analysis of PRA1 and its relationship to Candida albicans- macrophage interactions.","date":"2008","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/18625733","citation_count":46,"is_preprint":false},{"pmid":"28725901","id":"PMC_28725901","title":"Zinc binding sites in Pra1, a zincophore from Candida albicans.","date":"2017","source":"Dalton transactions (Cambridge, England : 2003)","url":"https://pubmed.ncbi.nlm.nih.gov/28725901","citation_count":37,"is_preprint":false},{"pmid":"16917502","id":"PMC_16917502","title":"PRA1 promotes the intracellular trafficking and NF-kappaB signaling of EBV latent membrane protein 1.","date":"2006","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16917502","citation_count":36,"is_preprint":false},{"pmid":"11373297","id":"PMC_11373297","title":"The cellular protein PRA1 modulates the anti-apoptotic activity of Epstein-Barr virus BHRF1, a homologue of Bcl-2, through direct interaction.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11373297","citation_count":34,"is_preprint":false},{"pmid":"28860090","id":"PMC_28860090","title":"The secreted Candida albicans protein Pra1 disrupts host defense by broadly targeting and blocking complement C3 and C3 activation fragments.","date":"2017","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28860090","citation_count":29,"is_preprint":false},{"pmid":"12768023","id":"PMC_12768023","title":"Interactions of rotavirus VP4 spike protein with the endosomal protein Rab5 and the prenylated Rab acceptor PRA1.","date":"2003","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/12768023","citation_count":28,"is_preprint":false},{"pmid":"11535589","id":"PMC_11535589","title":"Membrane topography and topogenesis of prenylated Rab acceptor (PRA1).","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11535589","citation_count":26,"is_preprint":false},{"pmid":"23068607","id":"PMC_23068607","title":"NDRG2 and PRA1 interact and synergistically inhibit T-cell factor/β-catenin signaling.","date":"2012","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/23068607","citation_count":19,"is_preprint":false},{"pmid":"20592422","id":"PMC_20592422","title":"Proteome-wide dysregulation by PRA1 depletion delineates a role of PRA1 in lipid transport and cell migration.","date":"2010","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/20592422","citation_count":17,"is_preprint":false},{"pmid":"29704397","id":"PMC_29704397","title":"Association of the hypha-related protein Pra1 and zinc transporter Zrt1 with biofilm formation by the pathogenic yeast Candida albicans.","date":"2018","source":"Microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29704397","citation_count":16,"is_preprint":false},{"pmid":"28487479","id":"PMC_28487479","title":"The Prenylated Rab GTPase Receptor PRA1.F4 Contributes to Protein Exit from the Golgi Apparatus.","date":"2017","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28487479","citation_count":15,"is_preprint":false},{"pmid":"11520070","id":"PMC_11520070","title":"Expression analysis and chromosomal assignment of PRA1 and RILP genes.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11520070","citation_count":14,"is_preprint":false},{"pmid":"16930546","id":"PMC_16930546","title":"Prenylated Rab acceptor 1 (PRA1) inhibits TCF/beta-catenin signaling by binding to beta-catenin.","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16930546","citation_count":12,"is_preprint":false},{"pmid":"16473601","id":"PMC_16473601","title":"Purification and properties of Yip3/PRA1 as a Rab GDI displacement factor.","date":"2005","source":"Methods in enzymology","url":"https://pubmed.ncbi.nlm.nih.gov/16473601","citation_count":12,"is_preprint":false},{"pmid":"28553273","id":"PMC_28553273","title":"Direct Binding of the pH-Regulated Protein 1 (Pra1) from Candida albicans Inhibits Cytokine Secretion by Mouse CD4+ T Cells.","date":"2017","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28553273","citation_count":11,"is_preprint":false},{"pmid":"31003775","id":"PMC_31003775","title":"Prenylated Rab acceptor RABAC1 inhibits anti-apoptotic protein BCL2A1 and induces apoptosis.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31003775","citation_count":10,"is_preprint":false},{"pmid":"15914857","id":"PMC_15914857","title":"PRA1 co-localizes with envelope but does not influence primate lentivirus production, infectivity or envelope incorporation.","date":"2005","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/15914857","citation_count":7,"is_preprint":false},{"pmid":"14604818","id":"PMC_14604818","title":"Pitfalls in the use of transfected overexpression systems to study membrane proteins function: the case of TSH receptor and PRA1.","date":"2003","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/14604818","citation_count":7,"is_preprint":false},{"pmid":"35627150","id":"PMC_35627150","title":"Analysis of the PRA1 Genes in Cotton Identifies the Role of GhPRA1.B1-1A in Verticillium dahliae Resistance.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/35627150","citation_count":4,"is_preprint":false},{"pmid":"33259547","id":"PMC_33259547","title":"Di-arginine and FFAT-like motifs retain a subpopulation of PRA1 at ER-mitochondria membrane contact sites.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/33259547","citation_count":3,"is_preprint":false},{"pmid":"39596637","id":"PMC_39596637","title":"Purification and Identification of the Nematicidal Activity of S1 Family Trypsin-Like Serine Protease (PRA1) from Trichoderma longibrachiatum T6 Through Prokaryotic Expression and Biological Function Assays.","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/39596637","citation_count":2,"is_preprint":false},{"pmid":"36325094","id":"PMC_36325094","title":"Allele frequency of SLC4A3 (PRA1), TTC8 (PRA2), and PRA-prcd mutations in golden retrievers in Brazil.","date":"2022","source":"Frontiers in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/36325094","citation_count":2,"is_preprint":false},{"pmid":"41315346","id":"PMC_41315346","title":"Structural insights into mechanisms of zinc scavenging by the Candida albicans zincophore Pra1.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41315346","citation_count":1,"is_preprint":false},{"pmid":"40503170","id":"PMC_40503170","title":"ADP ribosylation factor-like GTPase 6-interacting protein 5 (ARL6IP5): a prenylated Rab acceptor protein 1 (PRA1) family protein that shapes the ER membrane and regulates ER-phagy.","date":"2025","source":"Autophagy 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Pra1","date":"2025-01-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.09.632233","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.07.622448","title":"ER sensing of lipid metabolism drives PRA family-dependent regulation of COPII vesicle transport","date":"2024-11-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.07.622448","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18044,"output_tokens":3693,"usd":0.054763,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11286,"output_tokens":4076,"usd":0.079165,"stage2_stop_reason":"end_turn"},"total_usd":0.133928,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Yip3/PRA1 (RABAC1) acts catalytically as a GDI-displacement factor (GDF): it dissociates complexes of prenylated endosomal Rab GTPases (e.g., Rab9) bound to GDI and delivers them onto membranes. Purified Yip3/PRA1 protein reconstituted this GDF activity in vitro.\",\n      \"method\": \"Biochemical reconstitution with purified Yip3/PRA1 protein; in vitro GDF activity assay measuring Rab-GDI complex dissociation and membrane delivery\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified protein demonstrating catalytic GDF activity, replicated in a subsequent Methods in Enzymology paper (PMID:16473601)\",\n      \"pmids\": [\"14574414\", \"16473601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PRA1 (RABAC1) inhibits the extraction of membrane-bound Rab3A by GDI, opposing GDI-mediated Rab solubilization. PRA1 also binds weakly to GDI itself. Additionally, binding of Rab3A and VAMP2 to PRA1 is mutually exclusive: Rab3A can displace VAMP2 from a pre-formed VAMP2–PRA1 complex. The C-terminal domain of PRA1 is required for its soluble state; its deletion converts PRA1 into an integral membrane protein.\",\n      \"method\": \"Subcellular fractionation, immunocytochemistry, in vitro competition/binding assays, deletion mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (fractionation, pulldown, mutagenesis) in a single lab study\",\n      \"pmids\": [\"10751420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Mouse PRA1 (mPRA1) is a polytopic integral membrane protein with four transmembrane segments; all hydrophilic domains (N-terminus, inter-hydrophobic-domain linker, C-terminus) face the cytoplasm. The four TM segments act cooperatively during translocation/integration at the ER membrane.\",\n      \"method\": \"N-linked glycosylation scanning mutagenesis in intact cells and isolated microsomes; TM-segment substitution into a model membrane protein\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct topology mapping by glycosylation scanning and TM-substitution experiments, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"11535589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human PRA1 (RABAC1) interacts with multiple Rab GTPases: strong interaction with Rab4b, Rab5a, and Rab5c; weak interaction with Rab4a, Rab6, Rab7, Rab17, and Rab22. The protein (~185 aa) is distributed between cytosol and membranes.\",\n      \"method\": \"Yeast two-hybrid screening of human brain cDNA library; Western blot of overexpressed protein after fractionation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid only, single lab, no biochemical confirmation of direct binding\",\n      \"pmids\": [\"10329441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PRA1 (RABAC1) interacts with EBV anti-apoptotic protein BHRF1 (a Bcl-2 homolog). Two PRA1 regions (aa 30–53 and C-terminal 21 residues) mediate BHRF1 binding; two BHRF1 regions (aa 1–18 and 89–142, containing BH4 and BH1 domains) are required. PRA1 expression reduces the anti-apoptotic activity of BHRF1 but not of Bcl-2.\",\n      \"method\": \"Yeast two-hybrid screen; GST pull-down assay; co-immunoprecipitation; confocal laser scanning microscopy; deletion/domain mapping mutagenesis; cell viability/apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, GST pulldown, and functional rescue in one study; single lab\",\n      \"pmids\": [\"11373297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PRA1 (RABAC1) interacts with EBV oncoprotein LMP1 through LMP1's transmembrane domain, and colocalizes with LMP1 at the Golgi apparatus (colocalization sensitive to nocodazole and brefeldin A). PRA1 is required for proper intracellular trafficking of LMP1 and for LMP1-induced NF-κB activation; a PRA1 export mutant or PRA1 knockdown redistributes LMP1 to the ER and impairs NF-κB signaling, without affecting CD40- or TNFR1-mediated signaling or general Golgi integrity.\",\n      \"method\": \"Co-immunoprecipitation; immunofluorescence/confocal microscopy; nocodazole/brefeldin A treatment; PRA1 knockdown (RNAi); PRA1 export mutant overexpression; NF-κB luciferase reporter assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, knockdown with specific signaling readout, multiple orthogonal methods confirming Golgi-dependent trafficking role of PRA1 in LMP1 signaling\",\n      \"pmids\": [\"16917502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Rotavirus spike protein VP4 interacts with PRA1 (RABAC1). A VP4 domain spanning aa 560–722 is essential for both PRA1 and Rab5 interactions; deletion/site-directed mutants of VP4 can selectively abolish binding to one partner. Interactions were confirmed in infected and transfected cells.\",\n      \"method\": \"Yeast two-hybrid screen; co-immunoprecipitation from infected/transfected cell lysates; site-directed and deletion mutagenesis of VP4\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP from both infected and transfected cells plus domain mapping; single lab\",\n      \"pmids\": [\"12768023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PRA1 (RABAC1) binds β-catenin and inhibits TCF/β-catenin transcriptional signaling. PRA1 overexpression blocks nuclear translocation of β-catenin and reduces ERK1/2 phosphorylation. Deletion and site-directed PRA1 mutants and PRA1 siRNA confirmed these effects.\",\n      \"method\": \"Co-immunoprecipitation; confocal microscopy; TOPflash TCF luciferase reporter assay; site-directed and deletion mutagenesis; siRNA knockdown; nuclear fractionation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, reporter assay, mutagenesis, and knockdown converge on same conclusion; single lab\",\n      \"pmids\": [\"16930546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NDRG2 (and other NDRG family members) binds PRA1 (RABAC1). NDRG2 and PRA1 co-expressed together synergistically downregulate TCF promoter activity and reduce GSK3β phosphorylation more than either protein alone.\",\n      \"method\": \"Yeast two-hybrid screen; GST pull-down; co-immunoprecipitation; confocal microscopy; TCF luciferase reporter assay; GSK3β phosphorylation immunoblot\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST pulldown + Co-IP + functional reporter assay, single lab\",\n      \"pmids\": [\"23068607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PRA1 (RABAC1) depletion in NPC cells causes altered cell morphology, increased cell motility, and intracellular cholesterol accumulation. Proteins regulating lipid homeostasis and cell migration are upregulated upon PRA1 knockdown, and PRA1 overexpression can rescue dysregulation caused by either PRA1 knockdown or the cholesterol transport inhibitor U18666A. LMP1 expression sequesters PRA1 and phenocopies PRA1 knockdown effects on these proteins.\",\n      \"method\": \"Stable PRA1 knockdown cell clones; isobaric mass-tag labeling + multidimensional LC-MS proteomics; immunofluorescence staining; cholesterol staining; U18666A treatment; PRA1 overexpression rescue\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with specific cellular phenotypes (motility, cholesterol), proteomics, and rescue experiment; single lab\",\n      \"pmids\": [\"20592422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RABAC1/PRA1 binds the anti-apoptotic protein BCL2A1 and inhibits its anti-apoptotic function, inducing caspase-3 activation and apoptosis in AGS gastric cancer cells. RABAC1 also decreases cell proliferation, clonogenic survival, and cell migration/invasion.\",\n      \"method\": \"GST pull-down assay; co-immunoprecipitation; confocal microscopy; caspase-3 activity assay; clonogenic survival assay; cell migration/invasion assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST pulldown + Co-IP + functional apoptosis assays; single lab\",\n      \"pmids\": [\"31003775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"An endogenous subpopulation of PRA1 (RABAC1) resides at ER-mitochondria membrane contact sites. The cytosolic N-terminal region contains two ER retention/retrieval sequences: a membrane-distal di-arginine motif and a novel membrane-proximal FFAT-like motif. Mutation of either motif increases cell-surface localization; mutation of both has an additive effect. N- or C-terminal tagging of full-length PRA1 differentially redirects it to Golgi or reticular ER.\",\n      \"method\": \"Immunofluorescence and co-localization with ER/mitochondria markers in cultured mammalian cells; truncation and site-directed mutagenesis of retention motifs; flow cytometry for cell-surface expression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with mutagenesis establishing functional ER retention motifs; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33259547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In yeast, Yip3 (ortholog of RABAC1/PRA1) is a target gene of the Ino2/Ino4 transcription factors and negatively regulates COPII-mediated vesicle transport from the ER. Yip3 acts by hindering Sec16 assembly on the ER membrane (distinct from Ino2/Ino4, which regulates Sar1 activation). This places Yip3 as a downstream effector in an ER lipid-sensing pathway that fine-tunes anterograde vesicular transport.\",\n      \"method\": \"Genetic epistasis in yeast (Ino2/Ino4 pathway); Sec16 assembly assay on ER membranes; Sar1 activation assay; transcriptional reporter analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis with defined molecular readouts (Sec16 assembly, Sar1 activation); preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RABAC1 (PRA1/Yip3) is a four-pass transmembrane protein localized predominantly to the Golgi apparatus, with subpopulations at ER-mitochondria contact sites, whose best-characterized function is to act as a catalytic GDI-displacement factor (GDF) that dissociates prenylated Rab–GDI complexes and delivers Rab GTPases onto target membranes; it also interacts with VAMP2 (in a manner mutually exclusive with Rab binding), β-catenin (inhibiting TCF/β-catenin signaling), the anti-apoptotic proteins BHRF1 and BCL2A1 (reducing their anti-apoptotic activity), and the EBV oncoprotein LMP1 (facilitating LMP1 Golgi trafficking and NF-κB signaling), and regulates lipid transport and cell migration downstream of Rab-trafficking homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RABAC1 (PRA1/Yip3) is a polytopic, four-transmembrane integral membrane protein whose hydrophilic N-terminus, inter-domain linker, and C-terminus all face the cytoplasm [#2], and whose best-characterized role is to control the membrane association of Rab GTPases during vesicular trafficking. Acting catalytically as a GDI-displacement factor (GDF), purified RABAC1 dissociates prenylated Rab–GDI complexes and delivers Rab GTPases onto target membranes [#0]; it also opposes GDI-mediated extraction of membrane-bound Rab3A and binds Rab3A in a manner mutually exclusive with the SNARE VAMP2 [#1]. Its subcellular distribution is governed by an N-terminal di-arginine motif and a membrane-proximal FFAT-like motif that retain a subpopulation at ER–mitochondria contact sites, with loss of these motifs redirecting the protein toward the cell surface [#11]. Beyond Rab handling, RABAC1 serves as a trafficking adaptor and signaling modulator: it is required for Golgi trafficking of the EBV oncoprotein LMP1 and for LMP1-induced NF-κB activation [#5], binds β-catenin to block its nuclear translocation and inhibit TCF/β-catenin transcription [#7], and engages anti-apoptotic Bcl-2-family proteins BHRF1 and BCL2A1 to reduce their anti-apoptotic activity and promote caspase-3-dependent apoptosis [#4, #10]. Consistent with its trafficking role, RABAC1 depletion alters cell morphology, increases motility, and causes intracellular cholesterol accumulation [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that RABAC1 physically engages multiple Rab GTPases defined it as a candidate Rab-pathway regulator rather than an isolated trafficking protein.\",\n      \"evidence\": \"Yeast two-hybrid screen of human brain cDNA plus fractionation of overexpressed protein\",\n      \"pmids\": [\"10329441\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Yeast two-hybrid only, no biochemical confirmation of direct binding\", \"Functional consequence of each Rab interaction not defined\", \"Cytosol/membrane partitioning mechanism unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showing that PRA1 opposes GDI-mediated extraction of Rab3A and competes with VAMP2 reframed it as a regulator of the Rab membrane-cycling/SNARE interface.\",\n      \"evidence\": \"Subcellular fractionation, in vitro competition/binding assays, and deletion mutagenesis\",\n      \"pmids\": [\"10751420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GDI opposition reflects catalytic GDF activity not yet established here\", \"Physiological significance of VAMP2 displacement untested in vivo\", \"C-terminal control of solubility mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mapping the membrane topology established the structural framework for how cytosolic domains can engage Rabs and binding partners.\",\n      \"evidence\": \"N-linked glycosylation scanning and TM-substitution mutagenesis in cells and microsomes\",\n      \"pmids\": [\"11535589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure\", \"How cytosolic domains coordinate Rab vs partner binding unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying BHRF1 binding and reduction of its anti-apoptotic activity linked RABAC1 to apoptotic control via viral Bcl-2 homologs.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, reciprocal Co-IP, domain mapping, and viability assays\",\n      \"pmids\": [\"11373297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which binding lowers anti-apoptotic activity unclear\", \"Selectivity for BHRF1 over Bcl-2 unexplained\", \"Single lab\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"In vitro reconstitution with purified protein settled the central mechanistic question by demonstrating catalytic GDF activity that dissociates Rab–GDI complexes and delivers Rabs to membranes.\",\n      \"evidence\": \"Biochemical reconstitution with purified Yip3/PRA1 and an in vitro GDF assay\",\n      \"pmids\": [\"14574414\", \"16473601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Rab substrate specificity in cells not fully defined\", \"Structural basis of GDI displacement unknown\", \"Regulation of GDF activity in vivo unaddressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating rotavirus VP4 binding via a domain shared with Rab5 binding showed pathogens exploit the RABAC1 Rab interface during infection.\",\n      \"evidence\": \"Yeast two-hybrid plus Co-IP from infected and transfected cells with VP4 domain mapping\",\n      \"pmids\": [\"12768023\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role in the viral life cycle not established\", \"Whether VP4 and Rab5 compete for RABAC1 untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defining RABAC1 as required for LMP1 Golgi trafficking and NF-κB activation revealed a trafficking-adaptor role coupling cargo localization to signaling output.\",\n      \"evidence\": \"Reciprocal Co-IP, confocal imaging with nocodazole/BFA, RNAi, export mutant, and NF-κB reporter assays\",\n      \"pmids\": [\"16917502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GDF/Rab activity is needed for LMP1 trafficking not separated\", \"Generality to other Golgi-targeted cargo unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showing β-catenin binding and inhibition of TCF signaling extended RABAC1's reach into Wnt-pathway transcriptional control.\",\n      \"evidence\": \"Co-IP, confocal microscopy, TOPflash reporter, mutagenesis, and siRNA with nuclear fractionation\",\n      \"pmids\": [\"16930546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism blocking β-catenin nuclear entry undefined\", \"Relationship to membrane/Rab function unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linking PRA1 depletion to increased motility and cholesterol accumulation connected its trafficking function to lipid homeostasis and migration phenotypes.\",\n      \"evidence\": \"Stable knockdown clones, quantitative LC-MS proteomics, cholesterol staining, and rescue experiments\",\n      \"pmids\": [\"20592422\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link from Rab/GDF activity to cholesterol transport unproven\", \"Effector proteins driving migration not validated individually\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying NDRG2 as a partner that synergizes in downregulating TCF activity placed RABAC1 in a cooperative module of Wnt suppression.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, Co-IP, TCF reporter, and GSK3β phosphorylation immunoblot\",\n      \"pmids\": [\"23068607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical basis of synergy with NDRG2 unknown\", \"Connection to GSK3β regulation mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing BCL2A1 binding with induction of caspase-3 and reduced proliferation/invasion reinforced a pro-apoptotic, anti-tumor role through Bcl-2-family inhibition.\",\n      \"evidence\": \"GST pulldown, Co-IP, caspase-3 activity, clonogenic and migration/invasion assays in gastric cancer cells\",\n      \"pmids\": [\"31003775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of BCL2A1 inhibition undefined\", \"In vivo tumor relevance not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying an ER–mitochondria contact-site pool and dual N-terminal retention motifs explained how RABAC1 steady-state localization is controlled.\",\n      \"evidence\": \"Co-localization with ER/mitochondria markers, retention-motif mutagenesis, and surface-expression flow cytometry\",\n      \"pmids\": [\"33259547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function at contact sites unknown\", \"FFAT-like motif partner (e.g., VAP) not identified\", \"Relationship of localization to GDF activity untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Yeast Yip3 was shown to negatively regulate COPII transport by hindering Sec16 assembly, positioning the ortholog as an ER lipid-sensing effector of anterograde transport.\",\n      \"evidence\": \"Genetic epistasis in the Ino2/Ino4 pathway with Sec16 assembly and Sar1 activation assays (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab, not peer-reviewed\", \"Whether human RABAC1 regulates COPII similarly untested\", \"Mechanism of Sec16 inhibition not at molecular detail\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the catalytic GDF activity is mechanistically integrated with RABAC1's diverse non-Rab partners (β-catenin, Bcl-2 family, LMP1) and its contact-site localization remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of RABAC1 alone or with Rab/GDI\", \"Unclear whether signaling roles depend on or are independent of GDF activity\", \"Physiological Rab substrate repertoire in human cells undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VAMP2\", \"CTNNB1\", \"BHRF1\", \"BCL2A1\", \"NDRG2\", \"LMP1\", \"RAB3A\", \"RAB5A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}