RP2 is a ubiquitously expressed, N-terminally myristoylated and palmitoylated protein that associates with the cytoplasmic face of the plasma membrane and concentrates at the ciliary base (basal body, associated centriole and periciliary membrane) and Golgi. It is the specific GTPase-activating protein for the small GTPase ARL3: an arginine finger (Arg118) in its N-terminal beta-helix domain, which is homologous to the tubulin cofactor C, stimulates ARL3 GTP hydrolysis about 90,000-fold. By inactivating ARL3 outside the cilium RP2 keeps active ARL3 confined to the ciliary compartment and recycles the lipidated-cargo carriers UNC119B and PDE6D, enabling delivery of myristoylated and prenylated proteins (e.g., NPHP3, transducin, phosphodiesterase subunits) to the ciliary and photoreceptor outer segment membranes. RP2 also influences Golgi-to-cilium vesicle traffic. Loss-of-function mutations, including those of the arginine finger, cause X-linked retinitis pigmentosa.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000287 magnesium ion binding | IDA PMID:26455799 The Interaction of CCDC104/BARTL1 with Arl3 and Implications... | UNDECIDED | Summary: Magnesium ion binding attributed to RP2 from the BARTL1-ARL3 study. Reason: RP2 is a GAP with no known metal-binding site; Mg2+ is a cofactor of the ARL3 nucleotide-binding site and is part of the Arl3-GDP-AlF4 transition-state complex. The cached full text of PMID:26455799 does not mention magnesium binding by RP2, so the basis of this IDA cannot be verified here; it may reflect the ARL3 partner rather than RP2. Left undecided rather than removed because the curator may have used figure data. |
| GO:0005096 GTPase activator activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: GTPase activator activity inherited in the RP2/cofactor C clade. Reason: Consistent with direct biochemical demonstration of ARL3 GAP activity and conservation of the Cin4-Cin2 pair in yeast. Supporting Evidence: PMID:18376416 Biochemical analysis showing a 90,000-fold stimulation of the GTPase reaction together with the structure of an Arl3-GDP-AlF4--RP2 transition state complex showed that RP2 is an efficient GAP for Arl3, with structural features similar to other GAPs. PMID:18376416 The cognate G protein-GAP pair is conserved in yeast as Cin4-Cin2, and the ability of RP2 to act as a GAP can be correlated with its ability to complement a CIN2-deletion phenotype. |
| GO:0005096 GTPase activator activity | IDA PMID:11847227 Functional overlap between retinitis pigmentosa 2 protein an... | ACCEPT | Summary: RP2 with cofactor D stimulates tubulin GTPase activity via a conserved arginine. Reason: Direct assay of GTPase stimulation (of tubulin) by RP2; the arginine-finger mechanism is the same one later shown to drive ARL3 GAP activity, which is the physiological activity. Supporting Evidence: PMID:11847227 Here we show that in the presence of cofactor D, RP2 protein also stimulates the GTPase activity of tubulin. |
| GO:0005096 GTPase activator activity | IDA PMID:18376416 The retinitis pigmentosa 2 gene product is a GTPase-activati... | ACCEPT | Summary: RP2 is an efficient GAP for ARL3 (90,000-fold stimulation; transition-state structure). Reason: Definitive biochemical and structural evidence; core function. Supporting Evidence: PMID:18376416 Biochemical analysis showing a 90,000-fold stimulation of the GTPase reaction together with the structure of an Arl3-GDP-AlF4--RP2 transition state complex showed that RP2 is an efficient GAP for Arl3, with structural features similar to other GAPs. PMID:18376416 Furthermore, the effect of mutations in patients with retinitis pigmentosa correlated with their effect on catalysis, in particular the mutation of the arginine finger of RP2. file:human/RP2/RP2-deep-research-falcon.md RP2 is selective for ARL3 over the closely related ARL2. |
| GO:0005096 GTPase activator activity | IDA PMID:26455799 The Interaction of CCDC104/BARTL1 with Arl3 and Implications... | ACCEPT | Summary: RP2 acts as the ARL3-specific GAP that confines active ARL3 to cilia. Reason: Supports the ARL3 GAP activity in the ciliary context. Supporting Evidence: PMID:26455799 The exclusive localization of active Arl3 inside cilia is guaranteed by the Arl3-specific GTPase-activating protein RP2, which we find enriched around the basal body in IMCD3 cells (Figure S6A). |
| GO:0005096 GTPase activator activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based annotation (RP2 family). Reason: Consistent with experimental data. Supporting Evidence: PMID:18376416 Biochemical analysis showing a 90,000-fold stimulation of the GTPase reaction together with the structure of an Arl3-GDP-AlF4--RP2 transition state complex showed that RP2 is an efficient GAP for Arl3, with structural features similar to other GAPs. |
| GO:0005096 GTPase activator activity | TAS Reactome:R-HSA-5638007 | ACCEPT | Summary: Reactome: RP2 activates the GTPase activity of ARL3. Reason: Consistent with experimental data. Supporting Evidence: PMID:18376416 Biochemical analysis showing a 90,000-fold stimulation of the GTPase reaction together with the structure of an Arl3-GDP-AlF4--RP2 transition state complex showed that RP2 is an efficient GAP for Arl3, with structural features similar to other GAPs. |
| GO:0005515 protein binding | IPI PMID:11847227 Functional overlap between retinitis pigmentosa 2 protein an... | MODIFY | Summary: RP2 binds GTP-bound ARL3 (P36405). Reason: The interaction is the GAP-substrate/effector interaction with the small GTPase ARL3; small GTPase binding is more informative than protein binding. The catalytic consequence is captured by GTPase activator activity. Proposed replacements: small GTPase binding Supporting Evidence: PMID:11847227 Finally, we find that RP2 interacts with GTP-bound ADP ribosylation factor-like 3 protein |
| GO:0005515 protein binding | IPI PMID:16472755 Crystal structure of the human retinitis pigmentosa 2 protei... | MODIFY | Summary: Crystal structure and binding analysis of RP2 with (mouse) Arl3. Reason: RP2 is a specific ARL3 effector; replace generic protein binding with small GTPase binding. Proposed replacements: small GTPase binding Supporting Evidence: PMID:16472755 RP2 is a specific effector protein of Arl3. |
| GO:0005515 protein binding | IPI PMID:18376416 The retinitis pigmentosa 2 gene product is a GTPase-activati... | MODIFY | Summary: Arl3-GppNHp-RP2 complex structure; RP2 acts as GAP on Arl3. Reason: The paper establishes the binding as a GAP-GTPase interaction; GTPase activator activity is the informative term. Proposed replacements: GTPase activator activity Supporting Evidence: PMID:18376416 Biochemical analysis showing a 90,000-fold stimulation of the GTPase reaction together with the structure of an Arl3-GDP-AlF4--RP2 transition state complex showed that RP2 is an efficient GAP for Arl3, with structural features similar to other GAPs. |
| GO:0005515 protein binding | IPI PMID:26455799 The Interaction of CCDC104/BARTL1 with Arl3 and Implications... | MODIFY | Summary: RP2 forms an Arl3-GppNHp-RP2 complex displacing BARTL1. Reason: Binding of RP2 to active Arl3 is the GAP interaction; use GTPase activator activity. Proposed replacements: GTPase activator activity Supporting Evidence: PMID:26455799 The exclusive localization of active Arl3 inside cilia is guaranteed by the Arl3-specific GTPase-activating protein RP2, which we find enriched around the basal body in IMCD3 cells (Figure S6A). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput binary interactome hit (Q8IYS1). Reason: Generic protein binding from a proteome-scale yeast two-hybrid screen is uninformative and has no established functional context for RP2; removal does not imply the interaction is false. |
| GO:0005737 cytoplasm | IDA PMID:12417528 Localization in the human retina of the X-linked retinitis p... | ACCEPT | Summary: RP2 detected in the cytoplasm (cytoplasmic face of membranes) in retina/cells. Reason: RP2 is a peripheral membrane protein on the cytoplasmic side; cytoplasm is a correct broad location. Supporting Evidence: PMID:12417528 In human retina, RP2 was localized to the plasma membrane of cells throughout the retina. |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA annotation to cytoplasm. Reason: Correct broad location. Supporting Evidence: PMID:12417528 In human retina, RP2 was localized to the plasma membrane of cells throughout the retina. |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Golgi localization transferred from mouse. Reason: RP2 localizes to the Golgi in photoreceptors and its loss fragments the Golgi, but this is secondary to the plasma membrane/ciliary-base pools where it acts on ARL3. Supporting Evidence: PMID:20106869 RP2 also localized to the Golgi and periciliary ridge of photoreceptors, which suggested a role for RP2 in regulating vesicle traffic and docking. |
| GO:0005814 centriole | IEA GO_REF:0000107 | ACCEPT | Summary: Centriole localization transferred from mouse. Reason: RP2 localizes to the basal body and the associated centriole. Supporting Evidence: PMID:20106869 Here, we show that the retinitis pigmentosa protein RP2, which is a GTPase activating protein (GAP) for Arl3, localizes to the ciliary apparatus, namely the basal body and the associated centriole at the base of the photoreceptor cilium. |
| GO:0005886 plasma membrane | EXP PMID:10942419 Mutations in the N-terminus of the X-linked retinitis pigmen... | ACCEPT | Summary: RP2 targets to the plasma membrane via dual N-terminal acylation. Reason: Direct experimental evidence; plasma membrane is the main steady-state location. Supporting Evidence: PMID:10942419 Our data suggest that the protein is dually acylated and that the palmitoyl moiety is responsible for targeting of the myristoylated protein from intracellular membranes to the plasma membrane. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence: plasma membrane. Reason: Agrees with independent experimental localization (image not inspected). Supporting Evidence: PMID:10942419 Our data suggest that the protein is dually acylated and that the palmitoyl moiety is responsible for targeting of the myristoylated protein from intracellular membranes to the plasma membrane. |
| GO:0005886 plasma membrane | IDA PMID:12417528 Localization in the human retina of the X-linked retinitis p... | ACCEPT | Summary: RP2 at the plasma membrane of retinal cells including photoreceptors. Reason: Direct localization. Supporting Evidence: PMID:12417528 In human retina, RP2 was localized to the plasma membrane of cells throughout the retina. |
| GO:0005886 plasma membrane | IDA PMID:20106869 The retinitis pigmentosa protein RP2 links pericentriolar ve... | ACCEPT | Summary: RP2 plasma membrane localization in photoreceptors/cells. Reason: Consistent with other evidence. Supporting Evidence: PMID:10942419 Our data suggest that the protein is dually acylated and that the palmitoyl moiety is responsible for targeting of the myristoylated protein from intracellular membranes to the plasma membrane. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic plasma membrane annotation. Reason: Consistent with experimental evidence. Supporting Evidence: PMID:10942419 Our data suggest that the protein is dually acylated and that the palmitoyl moiety is responsible for targeting of the myristoylated protein from intracellular membranes to the plasma membrane. |
| GO:0005929 cilium | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: cilium localization. Reason: RP2 acts at the ciliary base/periciliary region to inactivate ARL3; the broad cilium term is acceptable. Supporting Evidence: PMID:20106869 Here, we show that the retinitis pigmentosa protein RP2, which is a GTPase activating protein (GAP) for Arl3, localizes to the ciliary apparatus, namely the basal body and the associated centriole at the base of the photoreceptor cilium. |
| GO:0005929 cilium | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to cilium. Reason: Consistent with ciliary-base localization. Supporting Evidence: PMID:20106869 Here, we show that the retinitis pigmentosa protein RP2, which is a GTPase activating protein (GAP) for Arl3, localizes to the ciliary apparatus, namely the basal body and the associated centriole at the base of the photoreceptor cilium. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5638004 | ACCEPT | Summary: Reactome: RP2 binds ARL3:GTP:UNC119B. Reason: Reactome cilium steps of the ARL3 cycle. Supporting Evidence: PMID:22085962 Strikingly, knockdown of ARL3, UNC119b, and RP2 each dramatically reduced the percentage of cilia with localized NPHP3 1–200. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5638006 | ACCEPT | Summary: Reactome: ARL3 hydrolyzes GTP. Reason: Reactome cilium steps of the ARL3 cycle. Supporting Evidence: PMID:22085962 Strikingly, knockdown of ARL3, UNC119b, and RP2 each dramatically reduced the percentage of cilia with localized NPHP3 1–200. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5638007 | ACCEPT | Summary: Reactome: RP2 activates ARL3 GTPase. Reason: Reactome cilium steps of the ARL3 cycle. Supporting Evidence: PMID:22085962 Strikingly, knockdown of ARL3, UNC119b, and RP2 each dramatically reduced the percentage of cilia with localized NPHP3 1–200. |
| GO:0005929 cilium | TAS Reactome:R-HSA-5638016 | ACCEPT | Summary: Reactome: RP2:ARL3:GDP:UNC119B dissociates. Reason: Reactome cilium steps of the ARL3 cycle. Supporting Evidence: PMID:22085962 Strikingly, knockdown of ARL3, UNC119b, and RP2 each dramatically reduced the percentage of cilia with localized NPHP3 1–200. |
| GO:0006457 protein folding | TAS PMID:9697692 Positional cloning of the gene for X-linked retinitis pigmen... | REMOVE | Summary: Protein folding inferred from homology of RP2 to tubulin folding cofactor C. Reason: This traceable-author statement rests only on sequence homology to cofactor C noted at cloning. Subsequent work established RP2 as an ARL3 GAP, and a curated NOT annotation (post-chaperonin tubulin folding pathway, IDA PMID:11847227) indicates RP2 does not act in tubulin folding. No evidence supports a protein-folding role. Supporting Evidence: PMID:9697692 The predicted gene product shows homology with human cofactor C, a protein involved in the ultimate step of beta-tubulin folding. PMID:18376416 Biochemical analysis showing a 90,000-fold stimulation of the GTPase reaction together with the structure of an Arl3-GDP-AlF4--RP2 transition state complex showed that RP2 is an efficient GAP for Arl3, with structural features similar to other GAPs. |
| GO:0006892 post-Golgi vesicle-mediated transport | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA: post-Golgi vesicle-mediated transport. Reason: RP2 depletion disperses Golgi-to-cilium vesicles, likely via ARL3 dysregulation; this is a downstream role rather than the core GAP-driven cargo-release cycle. Supporting Evidence: PMID:20106869 Depletion of RP2 and dysregulation of Arl3 resulted in dispersal of vesicles cycling cargo from the Golgi complex to the cilium, including the IFT protein IFT20. |
| GO:0006892 post-Golgi vesicle-mediated transport | IGI PMID:20106869 The retinitis pigmentosa protein RP2 links pericentriolar ve... | KEEP AS NON CORE | Summary: RP2 and ARL3 genetic interaction in pericentriolar vesicle transport. Reason: Experimental support exists; retained as non-core (acts upstream via ARL3). Supporting Evidence: PMID:20106869 Depletion of RP2 and dysregulation of Arl3 resulted in dispersal of vesicles cycling cargo from the Golgi complex to the cilium, including the IFT protein IFT20. |
| GO:0006892 post-Golgi vesicle-mediated transport | IMP PMID:20106869 The retinitis pigmentosa protein RP2 links pericentriolar ve... | KEEP AS NON CORE | Summary: RP2 depletion disperses vesicles cycling from Golgi to cilium. Reason: Experimental support exists; retained as non-core. Supporting Evidence: PMID:20106869 Depletion of RP2 and dysregulation of Arl3 resulted in dispersal of vesicles cycling cargo from the Golgi complex to the cilium, including the IFT protein IFT20. |
| GO:0007023 post-chaperonin tubulin folding pathway | IDA NOT PMID:11847227 Functional overlap between retinitis pigmentosa 2 protein an... | ACCEPT | Summary: NOT: RP2 does not function in the post-chaperonin tubulin folding pathway. Reason: The negative annotation is consistent with RP2 being an ARL3 GAP rather than a tubulin-folding cofactor, despite its partial functional overlap with cofactor C in tubulin GTPase stimulation. Supporting Evidence: PMID:11847227 Here we show that in the presence of cofactor D, RP2 protein also stimulates the GTPase activity of tubulin. |
| GO:0007601 visual perception | TAS PMID:9697692 Positional cloning of the gene for X-linked retinitis pigmen... | KEEP AS NON CORE | Summary: RP2 mutations cause X-linked retinitis pigmentosa. Reason: Disease genetics shows RP2 is needed for photoreceptor survival; visual perception is a high-level, indirect consequence of its role in photoreceptor ciliary trafficking. Supporting Evidence: PMID:9697692 Our data provide evidence that mutations in this gene, designated RP2, are responsible for progressive retinal degeneration. |
| GO:0031410 cytoplasmic vesicle | IGI PMID:20106869 The retinitis pigmentosa protein RP2 links pericentriolar ve... | KEEP AS NON CORE | Summary: RP2 associates with cytoplasmic (pericentriolar) vesicles. Reason: Supported but peripheral to the core function. Supporting Evidence: PMID:20106869 RP2 also localized to the Golgi and periciliary ridge of photoreceptors, which suggested a role for RP2 in regulating vesicle traffic and docking. |
| GO:0036064 ciliary basal body | IDA PMID:20106869 The retinitis pigmentosa protein RP2 links pericentriolar ve... | ACCEPT | Summary: RP2 localizes to the basal body in photoreceptors. Reason: Direct localization; key site of action. Supporting Evidence: PMID:20106869 Here, we show that the retinitis pigmentosa protein RP2, which is a GTPase activating protein (GAP) for Arl3, localizes to the ciliary apparatus, namely the basal body and the associated centriole at the base of the photoreceptor cilium. |
| GO:0036064 ciliary basal body | IDA PMID:26455799 The Interaction of CCDC104/BARTL1 with Arl3 and Implications... | ACCEPT | Summary: RP2 enriched around the basal body in IMCD3 cells. Reason: Direct localization. Supporting Evidence: PMID:26455799 The exclusive localization of active Arl3 inside cilia is guaranteed by the Arl3-specific GTPase-activating protein RP2, which we find enriched around the basal body in IMCD3 cells (Figure S6A). |
| GO:0036064 ciliary basal body | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic basal body annotation. Reason: Consistent with experimental data. Supporting Evidence: PMID:20106869 Here, we show that the retinitis pigmentosa protein RP2, which is a GTPase activating protein (GAP) for Arl3, localizes to the ciliary apparatus, namely the basal body and the associated centriole at the base of the photoreceptor cilium. |
| GO:0060271 cilium assembly | TAS Reactome:R-HSA-5624138 | MARK AS OVER ANNOTATED | Summary: Reactome cilium assembly pathway membership. Reason: RP2 is not required to build cilia; it regulates ARL3-dependent delivery of lipidated proteins to existing cilia. Inclusion in the broad Reactome "cilium assembly" pathway overstates its role. Supporting Evidence: PMID:22085962 Finally, we showed that ARL3, UNC119b (but not UNC119a), and the ARL3 GAP Retinitis Pigmentosa 2 (RP2) are required for NPHP3 ciliary targeting and that targeting requires UNC119b myristoyl-binding activity. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Urinary exosome proteomics. Reason: High-throughput detection in exosomes; not functionally informative for RP2. |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: B-cell exosome proteomics. Reason: High-throughput detection; not functionally informative. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: Prostatic secretion exosome proteomics. Reason: High-throughput detection; not functionally informative. |
| GO:1990075 periciliary membrane compartment | IBA GO_REF:0000033 | ACCEPT | Summary: IBA: periciliary membrane compartment. Reason: RP2 localizes to the photoreceptor periciliary ridge, the periciliary membrane compartment. Supporting Evidence: PMID:20106869 RP2 also localized to the Golgi and periciliary ridge of photoreceptors, which suggested a role for RP2 in regulating vesicle traffic and docking. |
| GO:1990075 periciliary membrane compartment | IEA GO_REF:0000107 | ACCEPT | Summary: Periciliary membrane compartment transferred from mouse. Reason: As above. Supporting Evidence: PMID:20106869 RP2 also localized to the Golgi and periciliary ridge of photoreceptors, which suggested a role for RP2 in regulating vesicle traffic and docking. |
| GO:1903441 protein localization to ciliary membrane | IMP PMID:22085962 An ARL3-UNC119-RP2 GTPase cycle targets myristoylated NPHP3 ... | NEW | Summary: Proposed NEW annotation. RP2 knockdown blocks ciliary membrane targeting of myristoylated NPHP3, as do ARL3 and UNC119B knockdown. Reason: RP2 performs the GTP-hydrolysis step that terminates each round of the ARL3-UNC119B cargo-release cycle and returns the carrier for reuse; Wright et al. describe this GTPase cycle as the mechanism that targets myristoylated cargo to the ciliary membrane. This places RP2 inside the localization process as a cycle component (GAP step) rather than as cargo. The module assigns RP2 to protein localization to cilium; the ciliary-membrane child is more precise. Caveat: RP2 could alternatively be modelled as a regulator of ARL3 activity only; this is flagged in suggested_questions. Supporting Evidence: PMID:22085962 Strikingly, knockdown of ARL3, UNC119b, and RP2 each dramatically reduced the percentage of cilia with localized NPHP3 1–200. PMID:22085962 Finally, we showed that ARL3, UNC119b (but not UNC119a), and the ARL3 GAP Retinitis Pigmentosa 2 (RP2) are required for NPHP3 ciliary targeting and that targeting requires UNC119b myristoyl-binding activity. |
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Download this section (compressed HTML)Q: Should RP2 be represented as a component of the ciliary lipidated-cargo targeting process, or only as a negative regulator of ARL3 activity?
Q: Is magnesium ion binding by RP2 itself supported by any direct data, or does the annotation derive from the ARL3 nucleotide site in the complex?
Q: How much of RP2 function in photoreceptors depends on its plasma membrane versus basal body/periciliary pools?
Experiment: Rescue RP2-null photoreceptors or RPE1 cells with acylation-site mutants or basal-body-tethered RP2 and measure ciliary NPHP3, transducin and PDE6 delivery.
Hypothesis: RP2 must be at the ciliary base (not only plasma membrane) to recycle UNC119B/PDE6D-ARL3 complexes.
Type: Targeted localization rescue
Experiment: Systematic GAP assays and binding measurements for patient variants with matched cellular rescue.
Hypothesis: All XLRP missense variants act by reducing ARL3 GAP activity or ARL3 binding.
Type: Variant biochemistry
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