RAB9A encodes a small GTPase of the Rab family that functions as a molecular switch cycling between GTP-bound active and GDP-bound inactive states. RAB9A is primarily localized to late endosomes and the trans-Golgi network (TGN) where it regulates retrograde transport of mannose-6-phosphate receptors (MPRs) from late endosomes to the TGN. This recycling pathway is essential for lysosome biogenesis as it returns MPRs to the TGN where they can capture newly synthesized lysosomal hydrolases. RAB9A uses multiple effectors including TIP47/PLIN3 for cargo selection, GCC185/GCC2 for vesicle tethering at the TGN, p40/RABEPK for transport regulation, and NDE1/NDEL1 for linking late endosomes to the dynein motor complex for microtubule-based retrograde transport. RAB9A also plays roles in melanosome biogenesis, phagosome maturation, and is exploited by various pathogens including HIV-1, filoviruses, and human papillomavirus during their replication cycles.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005764 lysosome | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation based on phylogenetic inference. RAB9A localizes to late endosomes and can be detected on lysosomes in mammalian cells as demonstrated by IDA evidence (PMID:15078902). Reason: Phylogenetically supported and consistent with experimental evidence. RAB9A's role in late endosome to TGN transport and its localization to late endosomal compartments supports lysosomal localization as part of its functional repertoire. Supporting Evidence: PMID:15078902 rabs 7 and 9 are present on late endosomes (and some lysosomes) |
| GO:0045335 phagocytic vesicle | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for phagocytic vesicle localization. Experimentally supported by IDA evidence showing RAB9A recruitment to phagosomes containing bacteria (PMID:21255211). Reason: Well-supported by experimental evidence. RAB9A is recruited to phagosomes containing S. aureus and M. tuberculosis, indicating genuine localization to phagocytic vesicles. Supporting Evidence: PMID:21255211 The phagosomes containing S. aureus were associated with 22 Rab GTPases |
| GO:0005770 late endosome | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for late endosome localization. This is the primary localization site for RAB9A, well-established by multiple experimental studies including PMID:8164745 and PMID:34793709. Reason: Core localization for RAB9A. The protein is primarily localized to late endosomes where it regulates retrograde transport to the TGN. This is the canonical localization for RAB9A. Supporting Evidence: PMID:8164745 Rab9 is localized primarily to late endosomes, where it aids the transport of mannose 6-phosphate receptors to the trans-Golgi network PMID:34793709 Rab9 is mainly located on late endosomes and required for their intracellular transport to trans-Golgi network (TGN) file:human/RAB9A/RAB9A-deep-research-falcon.md Rab9 depletion reduces late endosome diameter by approximately 45 percent |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProt subcellular location. RAB9A partially localizes to Golgi membranes as part of its function in endosome-to-TGN transport. Reason: Consistent with known function. RAB9A is involved in transport to the TGN and partially localizes to Golgi membranes. The more specific term trans-Golgi network membrane (GO:0032588) is also annotated and is more precise, but Golgi membrane is acceptable as a broader term. Supporting Evidence: PMID:34793709 Rab9 is mainly located on late endosomes and required for their intracellular transport to trans-Golgi network (TGN) |
| GO:0005770 late endosome | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation duplicating IBA annotation for late endosome. Both annotations are valid from different sources. Reason: Duplicate annotation from different sources (IEA vs IBA). Both are valid and supported by the well-established localization of RAB9A to late endosomes. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA annotation for ER membrane localization. While Rab proteins do transiently associate with ER as part of their biogenesis/prenylation cycle, ER is not a primary functional localization for RAB9A. Reason: ER membrane localization may reflect transient association during Rab protein biogenesis and prenylation, rather than a site of primary function. The core functional localizations for RAB9A are late endosomes and TGN. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA annotation for plasma membrane. Rab GTPases are lipid-anchored and can associate with multiple membrane compartments. This is not a primary functional site for RAB9A. Reason: Plasma membrane is not a primary functional localization for RAB9A. The core function is at late endosomes and TGN. This annotation may reflect general membrane association properties of prenylated Rab GTPases. |
| GO:0030659 cytoplasmic vesicle membrane | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for cytoplasmic vesicle membrane. This is a broader term that encompasses the more specific late endosome and transport vesicle localizations. Reason: Valid broader term. RAB9A is indeed found on cytoplasmic vesicle membranes, particularly late endosome-derived transport vesicles destined for the TGN. |
| GO:0030670 phagocytic vesicle membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation for phagocytic vesicle membrane. Supported by experimental evidence of RAB9A recruitment to phagosomes (PMID:21255211). Reason: Consistent with experimental evidence showing RAB9A localization to phagosomes containing bacteria. |
| GO:0031090 organelle membrane | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: IEA annotation for organelle membrane. This is a very general term. Reason: This term is too general to be informative. More specific membrane localizations (late endosome, TGN membrane, etc.) are already annotated and provide more useful information about RAB9A function. |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for cytoplasmic vesicle. This is a broad term that encompasses the more specific annotations. Reason: Acceptable as a broader term since RAB9A does localize to cytoplasmic vesicles, specifically late endosomes and transport vesicles. |
| GO:0042470 melanosome | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for melanosome localization. RAB9A has been shown to function in melanocyte cargo delivery to melanosomes based on mouse studies. Reason: Supported by functional data. RAB9A is required for proper trafficking of melanogenic enzymes to melanosomes in melanocytes, indicating functional localization to this organelle. |
| GO:0045335 phagocytic vesicle | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation duplicating IBA annotation for phagocytic vesicle. Reason: Duplicate annotation from different evidence sources. Both are valid and supported by experimental evidence (PMID:21255211). |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation based on ortholog transfer. X-ray crystallography shows RAB9A can form complexes where two RAB9A molecules are involved (PMID:34793709). Reason: Supported by structural data. The crystal structure of RAB9A-GTP with NDE1 shows that two RAB9A-GTP molecules lie on opposite sides of the NDE1 homodimer. Supporting Evidence: PMID:34793709 We determined the crystal structure of Rab9A-GTP in complex with the Rab9-binding region of Nde1 |
| GO:0042470 melanosome | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for melanosome localization based on mouse ortholog. Functional studies in mouse melanocytes support this localization. Reason: Well-supported by sequence similarity to mouse Rab9a which has been shown to function in melanosome biogenesis and cargo delivery. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8876191 | ACCEPT | Summary: TAS annotation from Reactome for cytosol localization. Rab GTPases cycle between membrane-bound active state and cytosolic GDP-bound inactive state. Reason: Consistent with Rab GTPase biology. The GDP-bound form of RAB9A is extracted from membranes by GDI and maintained in the cytosol before being redelivered to membranes. Supporting Evidence: PMID:8164745 A fraction of Rab proteins is present in the cytosol, bound with GDP, complexed to a protein termed GDI |
| GO:0032588 trans-Golgi network membrane | TAS Reactome:R-HSA-8876191 | ACCEPT | Summary: TAS annotation from Reactome for TGN membrane. RAB9A functions in transport to the TGN and localizes there via interaction with GCC185. Reason: Core functional localization. RAB9A mediates transport from late endosomes TO the TGN, and interacts with the TGN golgin GCC185/GCC2 to tether incoming vesicles. Supporting Evidence: PMID:18243103 GCC185 is a large coiled-coil protein at the trans Golgi network that is required for receipt of transport vesicles inbound from late endosomes |
| GO:0030133 transport vesicle | TAS Reactome:R-HSA-6814670 | ACCEPT | Summary: TAS annotation from Reactome for transport vesicle localization. RAB9A marks transport vesicles moving from late endosomes to TGN. Reason: Consistent with core function. RAB9A is found on transport vesicles that carry cargo (such as MPRs) from late endosomes to the TGN. |
| GO:0030133 transport vesicle | TAS Reactome:R-HSA-6814674 | ACCEPT | Summary: Duplicate TAS annotation from different Reactome reaction. Reason: Duplicate annotation from Reactome pathway curation. Valid and consistent with function. |
| GO:0030133 transport vesicle | TAS Reactome:R-HSA-6814675 | ACCEPT | Summary: Duplicate TAS annotation from different Reactome reaction. Reason: Duplicate annotation from Reactome pathway curation. Valid and consistent with function. |
| GO:0032588 trans-Golgi network membrane | TAS Reactome:R-HSA-6814671 | ACCEPT | Summary: Duplicate TAS annotation for TGN membrane from different Reactome reaction. Reason: Duplicate from Reactome. Valid and consistent with function. |
| GO:0032588 trans-Golgi network membrane | TAS Reactome:R-HSA-6814674 | ACCEPT | Summary: Duplicate TAS annotation for TGN membrane from different Reactome reaction. Reason: Duplicate from Reactome. Valid and consistent with function. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6814671 | ACCEPT | Summary: Duplicate TAS annotation for cytosol from different Reactome reaction. Reason: Duplicate from Reactome. Valid for Rab GTPase cycling mechanism. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9706390 | ACCEPT | Summary: Duplicate TAS annotation for cytosol from Reactome. Reason: Duplicate from Reactome. Valid for Rab GTPase cycling mechanism. |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: HDA annotation from high-throughput proteomics study identifying RAB9A in exosomes. Reason: High-throughput data annotation. While RAB9A may be detected in exosomes, this is not a core functional localization and may reflect contamination or incidental incorporation. Supporting Evidence: PMID:20458337 2010 May 11. MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis. |
| GO:0045335 phagocytic vesicle | IDA PMID:21255211 Rab GTPases regulating phagosome maturation are differential... | ACCEPT | Summary: IDA annotation demonstrating RAB9A localization to phagosomes containing S. aureus or M. tuberculosis. Reason: Direct experimental evidence. The study compared localization of 42 Rab GTPases to phagosomes and found RAB9A among those recruited to bacterial phagosomes. Supporting Evidence: PMID:21255211 The phagosomes containing S. aureus were associated with 22 Rab GTPases |
| GO:0005764 lysosome | IDA PMID:15078902 Cargo-selective endosomal sorting for retrieval to the Golgi... | ACCEPT | Summary: IDA annotation from study examining retromer and Rab protein localization in relation to endosome-to-Golgi retrieval. Reason: Direct experimental evidence showing RAB9A localization to lysosomes in addition to late endosomes. Supporting Evidence: PMID:15078902 rabs 7 and 9 are present on late endosomes (and some lysosomes) |
| GO:0005770 late endosome | IDA PMID:15078902 Cargo-selective endosomal sorting for retrieval to the Golgi... | ACCEPT | Summary: IDA annotation confirming late endosome localization using GFP-tagged Rab9 in HeLaM cells. Reason: Strong experimental evidence confirming the primary localization of RAB9A to late endosomes. Supporting Evidence: PMID:15078902 rabs 7 and 9 are present on late endosomes (and some lysosomes) |
| GO:0042147 retrograde transport, endosome to Golgi | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for retrograde transport from endosome to Golgi. This is the core biological process function of RAB9A. Reason: Core function. RAB9A is well-established as a key regulator of retrograde transport from late endosomes to the TGN, particularly for recycling mannose-6-phosphate receptors. Supporting Evidence: PMID:8164745 Rab9 is localized primarily to late endosomes, where it aids the transport of mannose 6-phosphate receptors to the trans-Golgi network PMID:34793709 Rab9 is mainly located on late endosomes and required for their intracellular transport to trans-Golgi network (TGN) |
| GO:0000166 nucleotide binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for nucleotide binding. True but overly general; more specific terms (GTP binding, GDP binding) are more informative. Reason: Valid but general. RAB9A binds both GTP and GDP as part of its GTPase cycle. More specific terms are also annotated. |
| GO:0003924 GTPase activity | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro domain mapping. GTPase activity is the core enzymatic function of RAB9A. Reason: Core molecular function. RAB9A hydrolyzes GTP to GDP as part of its regulatory cycle. This is supported by experimental evidence (PMID:15263003). Supporting Evidence: PMID:15263003 a tightly bound GDP molecule in the active site Knowledge gap: The specific GEF that activates RAB9A on late endosomes and the GAP that inactivates it have not been definitively identified, so how the RAB9A nucleotide switch is spatially and temporally controlled is unresolved. OPEN BIOLOGY RESIDUAL_SUBGAP Resolve: In vitro GEF assays across candidate DENN-domain GEFs and a TBC-domain GAP screen, with a CI-MPR mis-sorting readout on knockdown. "the specific guanine nucleotide exchange factor (GEF) that activates RAB9A and the GTPase-activating protein (GAP) that inactivates it have not been definitively identified" — file:human/RAB9A/RAB9A-deep-research-cyberian.md |
| GO:0003925 G protein activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for G protein activity based on EC number assignment. RAB9A functions as a regulatory GTPase. Reason: Valid annotation. RAB9A is a small GTPase that functions as a molecular switch in membrane trafficking, consistent with G protein activity. |
| GO:0005525 GTP binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation for GTP binding. Experimentally verified by crystal structure (PMID:34793709) and biochemical studies. Reason: Core molecular function. RAB9A binds GTP to become active and recruit effectors. Crystal structure confirms GTP binding (PMID:34793709). Supporting Evidence: PMID:34793709 We determined the crystal structure of Rab9A-GTP in complex with the Rab9-binding region of Nde1 |
| GO:0015031 protein transport | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation for protein transport. This is a broad process term; more specific terms like retrograde transport are more informative. Reason: Valid broader term. RAB9A regulates protein transport (specifically retrograde transport of MPRs from endosomes to TGN). |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: IEA annotation for hydrolase activity. This is a very general term; GTPase activity is more specific and informative. Reason: Too general. The more specific term GTPase activity (GO:0003924) is already annotated and is more informative for RAB9A function. |
| GO:0032482 Rab protein signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro for Rab protein signal transduction. This is the correct pathway category for RAB9A function. Reason: Appropriate biological process annotation. RAB9A participates in Rab-mediated signal transduction to regulate membrane trafficking. |
| GO:0005515 protein binding | IPI PMID:18787122 The Salmonella virulence protein SifA is a G protein antagon... | MODIFY | Summary: IPI annotation for interaction with PLEKHM2/SKIP. The study shows Rab9 binds SKIP and this interaction is antagonized by Salmonella SifA protein. Reason: Protein binding is too general. The study demonstrates specific interaction between RAB9A and SKIP (PLEKHM2), which should be captured by a more specific binding term if available, or the interaction should be recorded in the appropriate database. Proposed replacements: protein binding Supporting Evidence: PMID:18787122 SKIP's pleckstrin homology domain, which directly binds SifA, also binds to the late endosomal GTPase Rab9 |
| GO:0005515 protein binding | IPI PMID:23386062 Rac and Rab GTPases dual effector Nischarin regulates vesicl... | UNDECIDED | Summary: IPI annotation for interaction with NISCH (Nischarin). High-throughput interaction study. Reason: Unable to access the full text of PMID:23386062 to verify the specific interaction details. Supporting Evidence: PMID:23386062 Rac and Rab GTPases dual effector Nischarin regulates vesicle maturation to facilitate survival of intracellular bacteria. |
| GO:0005515 protein binding | IPI PMID:29568061 An AP-MS- and BioID-compatible MAC-tag enables comprehensive... | KEEP AS NON CORE | Summary: IPI annotation from high-throughput AP-MS/BioID study mapping protein interactions. Reason: High-throughput data. The generic protein binding annotation from systematic interactome mapping is less informative than specific interaction annotations. Supporting Evidence: PMID:29568061 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. |
| GO:0003925 G protein activity | IMP PMID:34793709 Nde1 is a Rab9 effector for loading late endosomes to cytopl... | ACCEPT | Summary: IMP annotation demonstrating G protein activity through mutational analysis of RAB9A-NDE1 interaction and its effect on dynein complex association. Reason: Strong experimental evidence. The study shows that GTP-bound RAB9A uses NDE1/NDEL1 as effector to control retrograde trafficking, demonstrating functional G protein activity. Supporting Evidence: PMID:34793709 the guanosine triphosphate (GTP)-bound Rab9A/B specifically uses Nde1/Ndel1 as an effector to interact with the dynein motor complex |
| GO:0003925 G protein activity | IDA PMID:8164745 Membrane targeting of the small GTPase Rab9 is accompanied b... | ACCEPT | Summary: IDA annotation from seminal study demonstrating Rab9 membrane targeting is accompanied by nucleotide exchange, a hallmark of G protein function. Reason: Foundational experimental evidence establishing RAB9A as a functional G protein. Supporting Evidence: PMID:8164745 this process is accompanied by endosome-triggered nucleotide exchange |
| GO:0006898 receptor-mediated endocytosis | IDA PMID:8164745 Membrane targeting of the small GTPase Rab9 is accompanied b... | MODIFY | Summary: IDA annotation for receptor-mediated endocytosis. However, RAB9A primarily functions in retrograde transport FROM endosomes TO the TGN, not in endocytosis per se. Reason: This annotation may be imprecise. RAB9A functions in recycling mannose-6-phosphate receptors from endosomes back to TGN, which is part of the receptor recycling pathway but distinct from the endocytic uptake step. The more accurate term would be retrograde transport, endosome to Golgi (GO:0042147). Proposed replacements: retrograde transport, endosome to Golgi Supporting Evidence: PMID:8164745 Membrane targeting of the small GTPase Rab9 is accompanied by nucleotide exchange. |
| GO:0005515 protein binding | IPI PMID:15471887 Interconnections of CLN3, Hook1 and Rab proteins link Batten... | UNDECIDED | Summary: IPI annotation for interaction with CLN3. Study examines connections between Batten disease protein CLN3, Hook1, and Rab proteins. Reason: Unable to access the full text of PMID:15471887 to verify the specific interaction details. Supporting Evidence: PMID:15471887 Oct 7. Interconnections of CLN3, Hook1 and Rab proteins link Batten disease to defects in the endocytic pathway. |
| GO:0005515 protein binding | IPI PMID:20048159 Assembly of the biogenesis of lysosome-related organelles co... | UNDECIDED | Summary: IPI annotation for interaction with HPS4 and BLOC-3 complex. Study demonstrates GTP-dependent binding of RAB9A to BLOC-3 components involved in lysosome-related organelle biogenesis. Reason: Unable to access the full text of PMID:20048159 to verify the specific interaction details and supporting text. Supporting Evidence: PMID:20048159 2010 Jan 4. Assembly of the biogenesis of lysosome-related organelles complex-3 (BLOC-3) and its interaction with Rab9. |
| GO:0032880 regulation of protein localization | IMP PMID:18787122 The Salmonella virulence protein SifA is a G protein antagon... | ACCEPT | Summary: IMP annotation from study on Salmonella SifA interaction with SKIP and Rab9. Shows Rab9 regulates LAMP1 distribution. Reason: Valid annotation. The study demonstrates that Rab9 and SKIP function to maintain peripheral LAMP1 distribution in cells, showing a role in protein localization. Supporting Evidence: PMID:18787122 both SKIP and Rab9 function to maintain peripheral LAMP1 distribution in cells |
| GO:0005515 protein binding | IPI PMID:22637480 RUTBC2 protein, a Rab9A effector and GTPase-activating prote... | UNDECIDED | Summary: IPI annotation for interaction with SGSM1/RUTBC2. Study identifies RUTBC2 as a Rab9A effector with GAP activity for Rab36. Reason: Unable to access the full text of PMID:22637480 to verify the specific interaction details. Supporting Evidence: PMID:22637480 2012 May 25. RUTBC2 protein, a Rab9A effector and GTPase-activating protein for Rab36. |
| GO:0005515 protein binding | IPI PMID:21808068 RUTBC1 protein, a Rab9A effector that activates GTP hydrolys... | MODIFY | Summary: IPI annotation for interaction with SGSM2/RUTBC1. Study shows RUTBC1 binds Rab9A-GTP and acts as GAP for Rab32 and Rab33B. Reason: Protein binding is too general. This effector interaction links Rab9A to regulation of other Rab GTPases. Proposed replacements: protein binding Supporting Evidence: PMID:21808068 RUTBC1 is a Tre2/Bub2/Cdc16 domain-containing protein that binds to Rab9A-GTP both in vitro and in cultured cells |
| GO:0005525 GTP binding | IDA PMID:21808068 RUTBC1 protein, a Rab9A effector that activates GTP hydrolys... | ACCEPT | Summary: IDA annotation demonstrating GTP binding by RAB9A, required for effector interactions. Reason: Direct experimental evidence. GTP binding is essential for RAB9A effector recruitment. Supporting Evidence: PMID:21808068 binds to Rab9A-GTP both in vitro and in cultured cells |
| GO:0019003 GDP binding | IDA PMID:20937701 Family-wide characterization of the DENN domain Rab GDP-GTP ... | ACCEPT | Summary: IDA annotation from study characterizing DENN domain Rab GDP-GTP exchange factors. GDP binding is confirmed by crystal structure (PMID:15263003). Reason: While this specific reference was not accessible, GDP binding is strongly supported by the crystal structure of RAB9A with GDP bound (PMID:15263003), confirming that RAB9A binds GDP as part of its GTPase cycle. Supporting Evidence: PMID:15263003 a tightly bound GDP molecule in the active site PMID:20937701 Oct 11. Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors. |
| GO:0045921 positive regulation of exocytosis | IMP PMID:19966785 Rab27a and Rab27b control different steps of the exosome sec... | UNDECIDED | Summary: IMP annotation from RNAi screen for Rab GTPases involved in exosome secretion. However, the primary finding was that Rab27a and Rab27b control exosome secretion, not Rab9. Reason: Unable to access the full text of PMID:19966785 to verify the specific evidence for RAB9A in exocytosis regulation. Supporting Evidence: PMID:19966785 2009 Dec 6. Rab27a and Rab27b control different steps of the exosome secretion pathway. |
| GO:0003924 GTPase activity | IDA PMID:15263003 High resolution crystal structure of human Rab9 GTPase: a no... | ACCEPT | Summary: IDA annotation from crystal structure study of human Rab9 with GDP bound. Reason: Strong structural evidence. The high-resolution crystal structure shows GDP bound in the active site, confirming GTPase activity. Supporting Evidence: PMID:15263003 a tightly bound GDP molecule in the active site |
| GO:0005515 protein binding | IPI PMID:18243103 Rab and Arl GTPase family members cooperate in the localizat... | MODIFY | Summary: IPI annotation for interaction with GCC185/GCC2 golgin. Study demonstrates Rab binding to GCC185 for TGN tethering. Reason: Protein binding is too general. This is a functionally critical effector interaction for vesicle tethering at the TGN. Proposed replacements: protein binding Supporting Evidence: PMID:18243103 GCC185 is a large coiled-coil protein at the trans Golgi network that is required for receipt of transport vesicles inbound from late endosomes |
| GO:0005525 GTP binding | IDA PMID:15263003 High resolution crystal structure of human Rab9 GTPase: a no... | ACCEPT | Summary: IDA annotation for GTP binding from crystal structure study. Structure shows nucleotide binding pocket. Reason: Strong structural evidence confirming GTP binding capability of RAB9A. Supporting Evidence: PMID:15263003 a characteristic nucleotide binding fold consisting of a six-stranded beta-sheet surrounded by five alpha-helices |
| GO:0019003 GDP binding | IDA PMID:15263003 High resolution crystal structure of human Rab9 GTPase: a no... | ACCEPT | Summary: IDA annotation for GDP binding from crystal structure with GDP bound. Reason: Direct structural evidence. Crystal structure was determined with GDP bound. Supporting Evidence: PMID:15263003 a tightly bound GDP molecule in the active site |
| GO:0005515 protein binding | IPI PMID:19490898 RhoBTB3 a Rho GTPase-family ATPase required for endosome to ... | UNDECIDED | Summary: IPI annotation for interaction with RHOBTB3. Study shows RHOBTB3 is required for endosome to Golgi transport and interacts with Rab9. Reason: Unable to access the full text of PMID:19490898 to verify the specific interaction details. Supporting Evidence: PMID:19490898 RhoBTB3: a Rho GTPase-family ATPase required for endosome to Golgi transport. |
| GO:0003924 GTPase activity | TAS PMID:9126495 Cloning and mapping of human Rab7 and Rab9 cDNA sequences an... | ACCEPT | Summary: TAS annotation from cDNA cloning paper establishing RAB9A as a Rab GTPase. Reason: Valid annotation establishing RAB9A identity as a Rab GTPase family member. Supporting Evidence: PMID:9126495 Cloning and mapping of human Rab7 and Rab9 cDNA sequences and identification of a Rab9 pseudogene. |
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Download this section (compressed HTML)Q: What are the specific GEFs and GAPs that regulate RAB9A activity in mammalian cells? While the RAB9A regulatory cycle is understood conceptually, the specific GEFs and GAPs have not been as well characterized as for other Rab GTPases like Rab7.
Q: How do RAB9A and retromer (VPS35/VPS26/VPS29) coordinate to ensure efficient MPR recycling? Both RAB9A and retromer have been implicated in endosome-to-TGN transport but they show limited colocalization. Understanding their functional relationship would clarify the retrograde transport machinery.
Experiment: CRISPR knockout of RAB9A in human cell lines followed by quantitative proteomics to identify changes in lysosomal enzyme delivery and MPR stability. This would provide definitive evidence for RAB9A function in human cells and identify additional cargo proteins affected by RAB9A loss.
Experiment: Live-cell imaging of RAB9A dynamics on late endosome-derived transport vesicles to characterize the temporal relationship with effector recruitment and fusion at TGN. This would provide mechanistic insight into the sequence of events during RAB9A-mediated retrograde transport.
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