RGS20

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005096 GTPase activator activity	IBA GO_REF:0000033	ACCEPT	Summary: RGS20 is a well-characterized GTPase-activating protein (GAP) that accelerates GTP hydrolysis on heterotrimeric G protein alpha subunits. This is the core biochemical function of RGS proteins, supported by direct biochemical assays demonstrating GAP activity with marked preference for Galpha-z over other Gi family members [PMID:9748279]. Reason: This annotation represents the core molecular function of RGS20. The protein was originally identified and characterized as a Gz-selective GAP. IBA annotations based on phylogenetic inference are appropriate for conserved RGS domain function. Supporting Evidence: PMID:9748279 Biochemical characterization of recombinant RGSZ1 protein revealed that RGSZ1 was indeed a GAP and, most significantly, showed a marked preference for Gzalpha over other members of the Gialpha family.
GO:0009898 cytoplasmic side of plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: RGS20 is anchored to membranes through palmitoylation at its N-terminal cysteine-rich region, allowing it to localize to the cytoplasmic face of the plasma membrane where it can interact with activated G protein alpha subunits [PMID:10791963, leung2017theroleof]. Reason: This annotation correctly describes the membrane localization mode of RGS20, which is consistent with its function in regulating membrane-associated GPCR signaling. Supporting Evidence: PMID:10791963 RGSZ, which shares with RGS-GAIP a cysteine-rich string in its N-terminal region, localized to the Golgi complex in COS-7 cells.
GO:0045744 negative regulation of G protein-coupled receptor signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: By accelerating GTP hydrolysis on Galpha subunits, RGS20 terminates GPCR signaling, acting as a negative regulator. Studies have shown it modulates mu-opioid receptor and melatonin MT1 receptor signaling [PMID:20859254, leung2017theroleof]. Reason: This represents a core biological function of RGS20. The negative regulatory role in GPCR signaling is the direct consequence of its GAP activity and is well supported by evidence from receptor-specific studies. Supporting Evidence: PMID:20859254 Here, we characterized the molecular complex of the melatonin MT₁ receptor, which directly and constitutively couples to G(i) proteins and the regulator of G-protein signalling (RGS) 20
GO:0003924 GTPase activity	IEA GO_REF:0000117	REMOVE	Summary: This IEA annotation is technically incorrect for RGS20. RGS proteins do not possess intrinsic GTPase activity; rather, they act as GTPase-activating proteins (GAPs) that enhance the intrinsic GTPase activity of Galpha subunits. RGS20 stimulates hydrolysis of GTP bound to Galpha-z/i but does not hydrolyze GTP itself. Reason: RGS20 does not have GTPase activity. It has GTPase activator activity (GAP activity), meaning it accelerates the GTPase activity of its substrates (Galpha-z, Galpha-i). This is a common over-annotation error where GAP function is confused with GTPase activity. The correct term is GO:0005096 (GTPase activator activity).
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: RGS20 has been shown to localize to the nucleus in addition to cytoplasm and membrane compartments. The protein shuttles between cytoplasm/membrane and nucleus [PMID:10791963, UniProt O76081]. Reason: Nuclear localization of RGS20 is documented in the literature and UniProt. This IEA annotation is consistent with experimental observations showing RGS proteins can localize to the nucleus. Supporting Evidence: PMID:10791963 These results demonstrate that RGS proteins localize in the nucleus, the cytoplasm, or shuttle between the nucleus and cytoplasm as nucleo-cytoplasmic shuttle proteins.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Cytoplasmic localization of RGS20 is well established and has been confirmed by experimental studies using confocal microscopy of GFP-tagged constructs [PMID:10791963]. Reason: This annotation is consistent with experimental evidence showing cytoplasmic pools of RGS20. Supporting Evidence: PMID:10791963 RGS proteins localize differentially within cells as a result of structural differences among these proteins that do not appear to be important determinants for their G protein-regulating activities
GO:0007186 G protein-coupled receptor signaling pathway	IEA GO_REF:0000117	ACCEPT	Summary: RGS20 is directly involved in GPCR signaling by modulating the duration and intensity of signaling through its GAP activity on Galpha subunits. Reason: This annotation is too general but not incorrect. RGS20 is a regulator of GPCR signaling pathways. The more specific term GO:0045744 (negative regulation of GPCR signaling) is already annotated and more informative.
GO:0009968 negative regulation of signal transduction	IEA GO_REF:0000043	ACCEPT	Summary: This is a broad parent term that encompasses the more specific function of RGS20 in negatively regulating GPCR signaling. Reason: While this annotation is correct, it is more general than the specific annotation for GPCR signaling pathway regulation. It is acceptable as a broader classification but the more specific term GO:0045744 is more informative.
GO:0016020 membrane	IEA GO_REF:0000044	ACCEPT	Summary: RGS20 associates with membranes via its N-terminal cysteine-rich region through palmitoylation. This is documented in UniProt and supported by experimental evidence. Reason: Membrane association of RGS20 is well-documented. While the more specific term GO:0009898 (cytoplasmic side of plasma membrane) is also annotated, this broader term is acceptable.
GO:0005515 protein binding	IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by...	MARK AS OVER ANNOTATED	Summary: This annotation derives from a large-scale IP-MS study of protein-protein interactions. RGS20 was identified in interaction screens, but this generic term does not provide functional insight. RGS20 binds specifically to Galpha-z/i subunits and GPCRs like the MT1 melatonin receptor [PMID:20859254]. Reason: 'Protein binding' is uninformative and should be replaced with more specific molecular function terms. RGS20's functional interactions are better captured by terms like 'G-protein alpha-subunit binding' or 'GTPase activator activity'. Supporting Evidence: PMID:17353931 We report the first large-scale study of protein-protein interactions in human cells using a mass spectrometry-based approach.
GO:0005515 protein binding	IPI PMID:20859254 Molecular organization and dynamics of the melatonin MT₁ rec...	MODIFY	Summary: This study characterized the MT1 receptor/RGS20/Gi protein complex, demonstrating direct physical interaction between RGS20 and the melatonin MT1 receptor. A more specific term would be appropriate. Reason: The study demonstrates specific receptor binding. A more appropriate annotation would be a term describing interaction with GPCRs or melatonin receptors. However, since specific GO terms for 'melatonin receptor binding' may not exist, this could be replaced with 'signaling receptor binding' (GO:0005102) or kept with annotation indicating the specific binding partner. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:20859254 Here, we characterized the molecular complex of the melatonin MT₁ receptor, which directly and constitutively couples to G(i) proteins and the regulator of G-protein signalling (RGS) 20
GO:0005515 protein binding	IPI PMID:21516116 Next-generation sequencing to generate interactome datasets.	MARK AS OVER ANNOTATED	Summary: This study describes a high-throughput method (Stitch-seq) for generating interactome datasets using next-generation sequencing. RGS20 was identified in interactions but generic protein binding is uninformative. Reason: High-throughput interactome studies provide evidence for interactions but the generic 'protein binding' term does not add functional information beyond what is captured by more specific terms. Supporting Evidence: PMID:21516116 We describe a massively parallel interactome-mapping pipeline, Stitch-seq, that combines PCR stitching with next-generation sequencing and used it to generate a new human interactome dataset
GO:0005515 protein binding	IPI PMID:23088713 Protein interactions of the transcription factor Hoxa1.	KEEP AS NON CORE	Summary: This study characterized the interactome of the transcription factor HOXA1 and identified RGS20 as an interactor. The interaction with HOXA1 may be biologically relevant given HOXA1's role in development. Reason: The HOXA1 interaction is documented in UniProt and may represent a real biological function, but 'protein binding' is uninformative. This interaction may not represent core RGS20 function as a GAP for G proteins. Supporting Evidence: PMID:23088713 RESULTS: To investigate the mode of action of mammalian Hoxa1, we characterized its interactome by a systematic yeast two-hybrid screening against ~12,200 ORF-derived polypeptides
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: This Cell paper describes a proteome-scale map of the human interactome network with approximately 14,000 high-quality binary protein-protein interactions. RGS20 interactions were identified as part of this systematic screen. Reason: While the interactions are valuable for understanding the RGS20 network, the generic 'protein binding' annotation provides no functional insight. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions
GO:0005515 protein binding	IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m...	MARK AS OVER ANNOTATED	Summary: This study developed an interactome perturbation framework to prioritize damaging missense mutations in developmental disorders. RGS20 was included in the interactome analysis. Reason: The study provides valuable network-level information but 'protein binding' annotation is too general to be informative about RGS20 function. Supporting Evidence: PMID:29892012 Here we establish an experimentally and computationally integrated approach to investigate the functional impact of missense mutations in the context of the human interactome network and test our approach by analyzing ~2,000 de novo missense mutations found in autism subjects and their unaffected siblings
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: This study examined disruption of protein interactions by genetic variants across the allele frequency spectrum. RGS20 was included in the systematic evaluation of protein-protein interactions. Reason: Generic protein binding annotation from high-throughput studies does not add functional insight. Supporting Evidence: PMID:31515488 To address this gap, we leverage the ExAC database of 60,706 human exomes to investigate experimentally the impact of 2009 missense single nucleotide variants (SNVs) across 2185 protein-protein interactions, generating interaction profiles for 4797 SNV-interaction pairs, of which 421 SNVs segregate at > 1% allele frequency in human populations
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: This study (BioPlex 3.0) created proteome-scale, cell-line-specific interaction networks through affinity-purification mass spectrometry, identifying 118,162 interactions in 293T cells. Reason: While the BioPlex network is a valuable resource, 'protein binding' is too generic to be informative about specific RGS20 function. Supporting Evidence: PMID:33961781 The first, BioPlex 3.0, results from affinity purification of 10,128 human proteins-half the proteome-in 293T cells and includes 118,162 interactions among 14,586 proteins
GO:0007186 G protein-coupled receptor signaling pathway	TAS Reactome:R-HSA-388396	ACCEPT	Summary: Reactome pathway annotation for GPCR downstream signaling. RGS20 participates in this pathway by regulating G protein activity. Reason: This Reactome-based annotation correctly places RGS20 in GPCR signaling pathways where it functions as a regulator of Galpha-z and Galpha-i signaling.
GO:0003924 GTPase activity	TAS Reactome:R-HSA-8982020	REMOVE	Summary: This Reactome annotation incorrectly assigns GTPase activity to RGS20. RGS20 does not hydrolyze GTP itself; it accelerates GTP hydrolysis by Galpha subunits. Reason: This is an incorrect annotation. RGS20 has GTPase activator (GAP) activity, not GTPase activity. The Galpha subunits (Galpha-z, Galpha-i) are the GTPases; RGS20 activates their intrinsic GTPase activity. This appears to be a Reactome curation error conflating the GAP with its substrate.
GO:0003924 GTPase activity	TAS Reactome:R-HSA-8982021	REMOVE	Summary: Same issue as above - incorrect assignment of GTPase activity to RGS20. Reason: RGS20 is a GTPase activator (GAP), not a GTPase. This annotation incorrectly attributes GTPase enzymatic activity to RGS20 rather than the Galpha subunits whose GTPase activity it enhances.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8981892	ACCEPT	Summary: Reactome annotation indicating plasma membrane localization, consistent with RGS20's role in modulating membrane-associated GPCR signaling. Reason: Plasma membrane localization is consistent with RGS20's function in regulating G protein signaling at the membrane and its palmitoylation-dependent membrane association.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8982012	ACCEPT	Summary: Duplicate plasma membrane annotation from Reactome pathway. Reason: This is a duplicate annotation with the same term but different Reactome reference. Both are acceptable as they correctly indicate plasma membrane localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8982018	ACCEPT	Summary: Duplicate plasma membrane annotation from Reactome pathway. Reason: Acceptable duplicate - correctly indicates plasma membrane localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8982019	ACCEPT	Summary: Duplicate plasma membrane annotation from Reactome pathway. Reason: Acceptable duplicate - correctly indicates plasma membrane localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8982020	ACCEPT	Summary: Duplicate plasma membrane annotation from Reactome pathway. Reason: Acceptable duplicate - correctly indicates plasma membrane localization.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-8982021	ACCEPT	Summary: Duplicate plasma membrane annotation from Reactome pathway. Reason: Acceptable duplicate - correctly indicates plasma membrane localization.
GO:0005802 trans-Golgi network	IMP PMID:10791963 Cytoplasmic, nuclear, and golgi localization of RGS proteins...	ACCEPT	Summary: The study by Chatterjee and Fisher (2000) showed that RGSZ (RGS20) localized to the Golgi complex in COS-7 cells. This localization is dependent on the N-terminal cysteine-rich region shared with RGS-GAIP. Reason: This is a well-documented experimental finding. The study specifically examined RGS protein localization using confocal microscopy of GFP fusion proteins and showed that RGSZ localized to the Golgi complex, distinct from other RGS proteins which showed cytoplasmic or nuclear localization. Supporting Evidence: PMID:10791963 RGSZ, which shares with RGS-GAIP a cysteine-rich string in its N-terminal region, localized to the Golgi complex in COS-7 cells.
GO:0005737 cytoplasm	IMP PMID:10791963 Cytoplasmic, nuclear, and golgi localization of RGS proteins...	ACCEPT	Summary: The same study demonstrated cytoplasmic localization of RGS proteins and showed that deletion of the N-terminal domain including the cysteine motif from RGSZ promoted nuclear localization, indicating the wild-type protein has cytoplasmic pools. Reason: Experimental evidence from confocal microscopy studies supports cytoplasmic localization of RGS20. Supporting Evidence: PMID:10791963 Deletion of the N-terminal domain of RGSZ that includes the cysteine motif promoted nuclear localization of RGSZ.
GO:0005096 GTPase activator activity	TAS PMID:9748279 RGSZ1, a Gz-selective regulator of G protein signaling whose...	ACCEPT	Summary: The original characterization of RGSZ1 (RGS20) by Glick et al. (1998) demonstrated that it acts as a GAP with marked preference for Galpha-z over other Galpha-i family members. This is the foundational paper establishing RGS20's biochemical function. Reason: This is the primary experimental evidence establishing RGS20 as a GTPase-activating protein. The biochemical characterization showed clear GAP activity toward Galpha-z with selectivity over other Gi family members. Supporting Evidence: PMID:9748279 Biochemical characterization of recombinant RGSZ1 protein revealed that RGSZ1 was indeed a GAP and, most significantly, showed a marked preference for Gzalpha over other members of the Gialpha family.
GO:0008277 regulation of G protein-coupled receptor signaling pathway	TAS PMID:9748279 RGSZ1, a Gz-selective regulator of G protein signaling whose...	ACCEPT	Summary: The study demonstrated that RGS20 regulates G protein signaling, consistent with its GAP activity toward Galpha-z. The phosphorylation state of Galpha-z affects susceptibility to RGS20 action. Reason: This annotation correctly describes RGS20's role as a regulator of GPCR signaling. While the more specific term GO:0045744 (negative regulation) may be more precise, this term is also appropriate and supported by the cited reference. Supporting Evidence: PMID:9748279 Phosphorylation of Gzalpha by protein kinase C, an event known to occur in cells and that was previously shown to influence alpha-betagamma interactions of Gz, rendered the G protein much less susceptible to RGSZ1 action.

Gene Description

Existing Annotations Review

Core Functions

RGS20 functions as a GTPase-activating protein (GAP) that accelerates the intrinsic GTPase activity of heterotrimeric G protein alpha subunits, particularly Galpha-z and Galpha-i1/i3. This is the core biochemical function of RGS20.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

📄 View Raw YAML