ARHGAP11B is a 267-residue human-specific protein that arose by partial duplication of the RhoGAP-encoding gene ARHGAP11A on the human lineage after the split from chimpanzee. Its first 220 residues are 98% identical to ARHGAP11A and carry most of a Rho-GAP fold, including the canonical catalytic arginine finger at position 87, but a single C-to-G substitution creates a novel splice donor site that removes 55 nucleotides, shifts the reading frame, and replaces the C-terminal end of the GAP domain with 47 residues found in no other known protein. The result is a protein that keeps the catalytic residue yet has no Rho GTPase-activating activity in cells, and the loss of that activity is not incidental damage: the reconstructed ancestral version, which retains GAP activity, does not do what the modern protein does. Instead of acting on Rho GTPases, ARHGAP11B carries an N-terminal targeting sequence into the mitochondrial matrix, where it binds the inner-membrane ADP/ATP translocases SLC25A4 and SLC25A5 and delays opening of the mitochondrial permeability transition pore. The resulting rise in mitochondrial calcium drives glutaminolysis, the routing of glutamine through glutamate into the tricarboxylic acid cycle, which is the metabolic state that proliferating cells require. In the fetal human neocortex the protein is expressed specifically in apical and basal radial glia and is absent from cortical neurons and cortical plate, and its effect there is to amplify basal progenitors in the subventricular zone, so that more upper-layer neurons are produced. Expressing it in mouse, ferret and marmoset neocortex increases basal progenitor proliferation, enlarges the neocortex and can induce cortical folding, while blocking or deleting it in human cerebral organoids drops basal progenitor levels to those of chimpanzee organoids. ARHGAP11B is therefore best understood not as a Rho regulator but as a mitochondrial metabolic modulator of neural progenitor proliferation, and the substitution that made it one is shared with Neanderthals and Denisovans and fixed in present-day humans.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005096 GTPase activator activity | IDA NOT PMID:25721503 Human-specific gene ARHGAP11B promotes basal progenitor ampl... | ACCEPT | Summary: A NOT annotation asserting that ARHGAP11B does not have Rho GTPase-activating activity. One of the best-founded rows in the record, and the key to the gene: the truncation that removed the activity is what made the protein able to amplify basal progenitors. Reason: The cached record for this paper is abstract-only and its abstract does not describe the RhoGAP assay, so I could not read the primary result directly. I did not treat that as grounds to doubt it. The full text of PMID:27957544 restates the result and cites this paper as its source, which independently confirms what the curator annotated. UniProt's recommended protein name, "Inactive Rho GTPase-activating protein 11B", and its CAUTION block record the same conclusion. Retained as a core, defining property of the gene product rather than a peripheral negative. Supporting Evidence: PMID:27957544 However, contrary to ARHGAP11A (27, 28), ARHGAP11B does not exhibit RhoGAP activity when expressed in monkey fibroblast-like cells (23). |
| GO:0005096 GTPase activator activity | IDA NOT PMID:27957544 A single splice site mutation in human-specific ARHGAP11B ca... | ACCEPT | Summary: The same NOT annotation from the paper that dissected the cause. Modern ARHGAP11B has no RhoGAP activity in cells, while the reconstructed ancestral protein, which has a complete GAP domain, does. Reason: Full text read. The paper establishes the negative and its mechanism in one experiment: ARHGAP11A-250 and ancestral ARHGAP11B are active in the MYPT1-pT853 assay, modern ARHGAP11B is not, and only modern ARHGAP11B amplifies basal progenitors. One qualification should travel with this row rather than be dropped: the authors report very low activity in a cell-free assay, so the claim is the absence of activity in intact cells, not an absolute zero under all conditions. NOT|enables remains the right encoding of that. The committed analysis in ARHGAP11B-bioinformatics corroborates this but is deliberately not the basis of the action. Projecting the GAP:GTPase interface of PDB 1TX4 onto ARHGAP11A, 2 of 24 mapped interface positions fall past the divergence point at residue 220 and so are absent from ARHGAP11B. Two positions out of 24 is a modest structural argument; the experiments are what carry this row. Supporting Evidence: PMID:27957544 Modern ARHGAP11B lacks RhoGAP activity in intact cells (23) and exhibits only very low RhoGAP activity in a cell-free assay. PMID:27957544 In contrast to modern ARHGAP11B, but similar to ARHGAP11A-250, ancestral ARHGAP11B was found to exhibit RhoGAP activity, as compared to a negative control (empty vector) (Fig. 2). |
| GO:0005096 GTPase activator activity | TAS Reactome:R-HSA-8981637 | REMOVE | Summary: Reactome asserts, by TAS, the exact molecular function that two independent IDA annotations on this same gene explicitly negate. GOA therefore ships a flat contradiction inside one gene's record, and the positive side carries the weaker evidence code. Reason: The source is a single Reactome reaction, "RHOA GAPs stimulate RHOA GTPase activity", whose catalyst is one set-level entity, "GTPase activator activity of RHOA GAPs [cytosol]". Querying QuickGO by this reference returns 43 annotations over 22 distinct entities, with 21 entities receiving GO:0005096 and 21 receiving GO:0005829, every one by TAS. So this is a bulk projection over a defined catalyst set rather than a judgement about ARHGAP11B, and ARHGAP11B is in that set because it looks like its paralog. For ARHGAP11A the same projection is correct and should stand. The removal is argued on biology, not on evidence-code snobbery. ARHGAP11B has no RhoGAP activity in cells (PMID:25721503, PMID:27957544), UniProt names it "Inactive Rho GTPase-activating protein 11B", and the loss is the gene's functional point. Note also what the removal does NOT rest on: the catalytic arginine finger is intact at position 87, so the usual pseudo-enzyme argument from missing catalytic residues is unavailable here and would have been a false reason for a correct action. The committed analysis in ARHGAP11B-bioinformatics confirms the arginine reciprocally against both ARHGAP11A's own annotated finger and ARHGAP1's structurally resolved one, requiring the aligned position to land on one of ARHGAP11B's own annotated sites. That analysis also shows why the residue is a poor discriminator here at all: of the 6 reviewed human RhoGAP-profile proteins whose annotated finger position is not an arginine, only one (OCRL) carries an experimentally supported UniProt statement that the domain is inactive, three are silent, and ARHGAP36 is asserted to be an active GTPase activator by similarity despite a threonine at that position. Residue identity and curated activity are decoupled in both directions in this family. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG PSEUDO OR SUBACTIVITY LOSS Sources checked: Reactome:R-HSA-8981637 · Reactome reaction "RHOA GAPs stimulate RHOA GTPase activity" SUPPORTS SOURCE BUT NOT TARGET The reaction correctly describes RHOA GAPs as a class and its catalyst is a defined set; 21 entities receive GO:0005096 from it by TAS. The error is including a GAP-dead paralog in the set, not the reaction. UniProtKB:Q6P4F7 · human ARHGAP11A (the paralog ARHGAP11B was duplicated from) SUPPORTS SOURCE BUT NOT TARGET ARHGAP11A genuinely has this activity, by IDA from PMID:27957544 and by IBA from PANTHER node PTN001038329. ARHGAP11B is 98% identical to it over residues 1-220 and shares its PANTHER subfamily PTHR15670:SF4, which is why it is mistaken for a RHOA GAP. The same paper that gave ARHGAP11A the positive IDA gave ARHGAP11B the negated one. Supporting Evidence: PMID:27957544 However, contrary to ARHGAP11A (27, 28), ARHGAP11B does not exhibit RhoGAP activity when expressed in monkey fibroblast-like cells (23). |
| GO:0005515 protein binding | IPI PMID:31883789 Human-Specific ARHGAP11B Acts in Mitochondria to Expand Neoc... | MODIFY | Summary: Interaction with SLC25A5 (ANT2), one of the two inner-mitochondrial-membrane ADP/ATP translocases through which ARHGAP11B acts. This is the mechanism of the gene, not screen noise, so the uninformative parent term should be replaced rather than dropped. Reason: The partner accession resolves to reviewed canonical Swiss-Prot SLC25A5, with no TrEMBL or partial-ORFeome substitution. The interaction is corroborated by UniProt's SUBUNIT line (ECO:0000269|PubMed:31883789) and is topologically coherent: ARHGAP11B carries a mitochondrial transit peptide and is located in the matrix, which is where an ANT-facing partner has to be. GO:0005515 states none of this. SLC25A5 is a transmembrane transporter, so GO:0044325 transmembrane transporter binding is an evidence-backed and informative replacement that stays within what the cited paper shows. I stopped short of GO:0141110 transporter inhibitor activity even though the paper's logic points that way, because the cached record is abstract-only and "inhibits the mPTP" is not the same claim as "inhibits ANT-mediated transport". That is raised for a curator with the full text rather than resolved here. Proposed replacements: transmembrane transporter binding Supporting Evidence: PMID:31883789 Here, we show that ARHGAP11B is imported into mitochondria, where it interacts with the adenine nucleotide translocase (ANT) and inhibits the mitochondrial permeability transition pore (mPTP). |
| GO:0005515 protein binding | IPI PMID:31883789 Human-Specific ARHGAP11B Acts in Mitochondria to Expand Neoc... | MODIFY | Summary: Interaction with SLC25A4 (ANT1), the second ADP/ATP translocase named in the same study. Judged on its own rather than inherited from the SLC25A5 row, though the two resolve the same way. Reason: Same reasoning as the SLC25A5 row, and deliberately reached separately: the partner resolves to reviewed canonical Swiss-Prot SLC25A4 of the expected length, UniProt records both translocases in a single SUBUNIT statement attributed to this paper, and both are inner-membrane transporters accessible from the matrix. Nothing in the available evidence distinguishes the two partners, so both take the same replacement term. ANT1 and ANT2 are paralogous isoforms of the same carrier, so a single interaction experiment reporting both is expected rather than suspicious. Proposed replacements: transmembrane transporter binding Supporting Evidence: PMID:31883789 Here, we show that ARHGAP11B is imported into mitochondria, where it interacts with the adenine nucleotide translocase (ANT) and inhibits the mitochondrial permeability transition pore (mPTP). |
| GO:0005759 mitochondrial matrix | IDA PMID:31883789 Human-Specific ARHGAP11B Acts in Mitochondria to Expand Neoc... | ACCEPT | Summary: Direct localisation of ARHGAP11B to the mitochondrial matrix. This is the core localisation of the protein and it is what makes every other part of its mechanism possible. Reason: The cached record is abstract-only, and the granularity is worth stating precisely because the quotes below cannot carry it: the abstract establishes import into MITOCHONDRIA, not into the matrix specifically. The sub-compartment comes from the full text, via UniProt's curated SUBCELLULAR LOCATION of Mitochondrion matrix attributed to ECO:0000269|PubMed:31883789, and the entry also carries a predicted N-terminal mitochondrial transit peptide, which is consistent with matrix import rather than with an outer-membrane or intermembrane-space pool. Accepting the matrix term therefore defers to a curator who read the full text, which is the correct default. The abstract does independently show that the progenitor phenotype requires the protein to be in mitochondria, so the localisation is functionally tested and not a bare imaging result. Accepted as core. Supporting Evidence: PMID:31883789 BP expansion by ARHGAP11B requires its presence in mitochondria, and pharmacological inhibition of ANT function or mPTP opening mimic BP expansion by ARHGAP11B. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: Automatic mapping of UniProt's curated SUBCELLULAR LOCATION keyword onto the same GO term. Duplicates the IDA row, which is fine. Reason: The SubCell term SL-0170 is mitochondrion matrix, and the UniProt location it maps is itself attributed to PubMed:31883789, so this row is a mechanical restatement of the curated experimental call rather than an independent inference that could drift from it. Duplicate GO ids across evidence codes are not a defect. Marked ACCEPT rather than demoted because the term is exactly right; it simply adds no information the IDA row does not already carry. As on that row, the matrix sub-compartment rests on the full text via UniProt's curated location, not on the abstract, which says only that the protein is imported into mitochondria. Supporting Evidence: PMID:31883789 Here, we show that ARHGAP11B is imported into mitochondria, where it interacts with the adenine nucleotide translocase (ANT) and inhibits the mitochondrial permeability transition pore (mPTP). |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8981637 | REMOVE | Summary: A cytosol annotation produced by the same Reactome reaction as the contradicted GAP-activity row, and by the same mechanism: the compartment is the reaction's, not a measurement of where ARHGAP11B is. Reason: R-HSA-8981637 is annotated to the cytosol and plasma membrane compartments, and every one of the 21 entities that receives GO:0005096 from it also receives GO:0005829 from it, by TAS. A Reactome compartment label is a property of the reaction, not an observation about a participant. Here the participation itself is wrong, so the compartment falls with it. The positive evidence points elsewhere: ARHGAP11B is imported into the mitochondrial matrix by IDA, UniProt lists Mitochondrion matrix as its only subcellular location, and the same study that localised ARHGAP11B to mitochondria localised ARHGAP11A to the nucleus (GO:0005634 IDA) - so the shared cytosol call describes neither paralog. A transit-peptide-bearing protein does of course pass through the cytosol before import, but that is not what this annotation records, and nothing measures a functional cytosolic pool. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: Reactome:R-HSA-8981637 · Reactome reaction "RHOA GAPs stimulate RHOA GTPase activity" SUPPORTS SOURCE BUT NOT TARGET 21 entities receive GO:0005829 from this one reaction by TAS, matching the 21 that receive GO:0005096. The compartment travels with set membership rather than being observed on any member. Deliberately NOT tagged WRONG_ORTHOLOG_OR_PARALOG, unlike the GO:0005096 row: the cytosol call is wrong for ARHGAP11A too, which has a nucleus IDA, so this is not a paralog-transfer error but a compartment asserted from a reaction's own annotation. Supporting Evidence: PMID:31883789 Here, we show that ARHGAP11B is imported into mitochondria, where it interacts with the adenine nucleotide translocase (ANT) and inhibits the mitochondrial permeability transition pore (mPTP). |
| GO:0006543 L-glutamine catabolic process | IDA PMID:31883789 Human-Specific ARHGAP11B Acts in Mitochondria to Expand Neoc... | ACCEPT | Summary: ARHGAP11B drives glutaminolysis in neural progenitors. The acts_upstream_of_positive_effect qualifier is the correct encoding: the protein is not a glutaminase, it induces the pathway through its effect on mitochondrial calcium. Reason: The abstract states that basal progenitor expansion by ARHGAP11B requires glutaminolysis, the conversion of glutamine to glutamate for the TCA cycle, and the curator has been careful to encode an upstream positive effect rather than an enzymatic involvement. That distinction matters here, because ARHGAP11B has no catalytic activity of any kind. Accepted as a core part of the mechanism. The cached record is abstract-only; the claim is in the abstract and I did not refine the term beyond what it states. Supporting Evidence: PMID:31883789 Searching for the underlying metabolic basis, we find that BP expansion by ARHGAP11B requires glutaminolysis, the conversion of glutamine to glutamate for the tricarboxylic acid (TCA) cycle. |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | REMOVE | Summary: A signal-transduction term derived automatically from the RhoGAP domain signature. The signature matches, but the activity it stands for is experimentally absent from this protein and its actual role is mitochondrial metabolism. Reason: IPR000198 is the RhoGAP domain. The interpro2go mapping from that signature to GO:0007165 is reasonable for RhoGAPs in general and wrong for this one, for the same reason the Reactome GAP row is wrong: the domain is present, the function is not. ARHGAP11B has no RhoGAP activity in cells, carries a NOT annotation for positive regulation of GTPase activity, and acts inside the mitochondrial matrix on the permeability transition pore, which is not signal transduction on any reading. This gene also shows how the signature comes to match so convincingly. UniProt's Rho-GAP DOMAIN feature on ARHGAP11B spans 49..250, which is 30 residues past residue 220, the last residue homologous to ARHGAP11A, and therefore extends into the human-specific frameshift C-terminus. The consequence is that the annotated domain on the inactive truncated paralog (202 aa) is 11 residues LONGER than the annotated domain on the catalytically active parent ARHGAP11A (49..239, 191 aa). Any automated step that reads domain extent as evidence of an intact RhoGAP reads this protein as more intact than the active one. Measured in ARHGAP11B-bioinformatics, where the divergence point at 220 is fitted as a changepoint with its significance set by permutation rather than by a chosen identity cutoff. Propagation Review Root cause: PROPAGATION BAD Failure modes: PSEUDO OR SUBACTIVITY LOSS FUNCTIONAL DIVERGENCE Sources checked: InterPro:IPR000198 · Rho GTPase-activating protein domain SUPPORTS SOURCE BUT NOT TARGET The signature genuinely matches ARHGAP11B, and the interpro2go line is defensible for the RhoGAP family as a whole. It fails on a family member that has kept the fold and the arginine finger while losing the activity, and whose annotated domain boundary overruns into non-homologous sequence. Supporting Evidence: PMID:27957544 Thus, the single C→G base change in the ARHGAP11B gene is ultimately the reason for the reading frame shift that leads to the truncation of the GAP domain of ARHGAP11B and its novel C-terminal sequence (amino acids 221 to 267; Fig. 1 and fig. S2), which is unique to ARHGAP11B and not found in any other protein thus far described in the animal kingdom |
| GO:0021987 cerebral cortex development | IDA PMID:25721503 Human-specific gene ARHGAP11B promotes basal progenitor ampl... | ACCEPT | Summary: The founding observation: ARHGAP11B is expressed in human fetal radial glia and, expressed in embryonic mouse neocortex, promotes basal progenitor generation and self-renewal and can induce gyrification. Reason: Core. The human-side evidence here is expression, radial-glia-specific, in fetal human neocortex, while the functional demonstration is gain-of-function in mouse by in utero electroporation. The gene product assayed is the human protein, so an experimental code is appropriate, but the system should be read as mouse neocortex rather than human tissue. The term is correct and is kept; a more specific process term covering what the protein actually does to progenitors is proposed additively below rather than by modifying this row. Supporting Evidence: PMID:25721503 Expression of ARHGAP11B in embryonic mouse neocortex promotes basal progenitor generation and self-renewal and can increase cortical plate area and induce gyrification. |
| GO:0021987 cerebral cortex development | IDA PMID:27957544 A single splice site mutation in human-specific ARHGAP11B ca... | ACCEPT | Summary: The same process from the splice-site paper, which additionally shows that the effect belongs to modern ARHGAP11B and not to the reconstructed ancestral protein. Reason: Core, and evidentially the strongest of the four cerebral-cortex rows, because it includes an internal negative control that no other row has: ancestral ARHGAP11B, differing by the single substitution, has no effect on mitotic basal progenitor abundance. That rules out the possibility that the phenotype is a generic consequence of overexpressing a RhoGAP-like protein. System is embryonic mouse neocortex by in utero electroporation. Supporting Evidence: PMID:27957544 Confirming our previous results (23), modern ARHGAP11B expression resulted in an increase of approximately twofold in targeted mitotic BPs, as compared to control (Fig. 3). PMID:27957544 However, similar to ARHGAP11A (23), ancestral ARHGAP11B did not exert any effect on mitotic BP abundance (Fig. 3). |
| GO:0021987 cerebral cortex development | IDA PMID:31883789 Human-Specific ARHGAP11B Acts in Mitochondria to Expand Neoc... | ACCEPT | Summary: The same process, established here through the mitochondrial mechanism: the progenitor effect requires the protein to be in mitochondria and requires glutaminolysis. Reason: Core. This row is not a duplicate of the other three in substance - it is the one that ties the cortical phenotype to a molecular mechanism, by showing that removing the protein from mitochondria abolishes the effect and that pharmacological mimicry of ANT or mPTP inhibition reproduces it. Cached record is abstract-only and the claim is in the abstract. Supporting Evidence: PMID:31883789 BP expansion by ARHGAP11B requires its presence in mitochondria, and pharmacological inhibition of ANT function or mPTP opening mimic BP expansion by ARHGAP11B. |
| GO:0021987 cerebral cortex development | IDA PMID:33938018 Expression of human-specific ARHGAP11B in mice leads to neoc... | ACCEPT | Summary: The same process in a transgenic mouse expressing ARHGAP11B at physiological rather than overexpression levels, with the neocortical enlargement persisting into adulthood. Reason: Core, and the row that answers the standard objection to all the others. Every earlier cerebral-cortex annotation rests on acute overexpression; this one uses a transgenic line at physiological expression levels and shows the enlarged neocortex and increased upper-layer neuron numbers persist to P56. The system is mouse carrying the human transgene, so the result is a property of the human protein acting in mouse neocortex. The accompanying neurobehavioural findings are downstream consequences in the mouse and are deliberately not proposed as annotations of this gene product. Supporting Evidence: PMID:33938018 Here, we generated a transgenic mouse line with physiological ARHGAP11B expression that exhibits increased neocortical size and upper-layer neuron numbers persisting into adulthood. |
| GO:0035795 negative regulation of mitochondrial membrane permeability | IDA PMID:31883789 Human-Specific ARHGAP11B Acts in Mitochondria to Expand Neoc... | ACCEPT | Summary: ARHGAP11B delays opening of the mitochondrial permeability transition pore through its interaction with the adenine nucleotide translocase. This is the proximate molecular consequence of the protein being in the matrix. Reason: One of the best-fitted terms in this record: the definition, any process that decreases the passage or uptake of molecules by the mitochondrial membrane, is exactly what inhibiting mPTP opening does, and the direction is right, since ARHGAP11B inhibits the pore. Core. The cached record is abstract-only and the claim is stated there; I did not refine it to a pore-specific child on evidence I cannot read in full. Supporting Evidence: PMID:31883789 Here, we show that ARHGAP11B is imported into mitochondria, where it interacts with the adenine nucleotide translocase (ANT) and inhibits the mitochondrial permeability transition pore (mPTP). |
| GO:0043547 positive regulation of GTPase activity | IDA NOT PMID:27957544 A single splice site mutation in human-specific ARHGAP11B ca... | ACCEPT | Summary: The process-side counterpart of the negated molecular function: ARHGAP11B does not positively regulate GTPase activity. Reason: Correct and well-evidenced, and worth keeping alongside the MF negation because it blocks the process-branch inference independently. Note the internal consistency of the UniProt curation across the paralogs, which is what makes this record trustworthy: from this very paper, ARHGAP11A received GO:0043547 involved_in by IDA while ARHGAP11B received the negated form. The curator read one experiment and annotated the two paralogs in opposite directions, which is exactly right. Supporting Evidence: PMID:27957544 However, contrary to ARHGAP11A (27, 28), ARHGAP11B does not exhibit RhoGAP activity when expressed in monkey fibroblast-like cells (23). PMID:27957544 Modern ARHGAP11B lacks RhoGAP activity in intact cells (23) and exhibits only very low RhoGAP activity in a cell-free assay. |
| GO:0051056 regulation of small GTPase mediated signal transduction | TAS Reactome:R-HSA-9012999 | REMOVE | Summary: Pathway-membership annotation placing ARHGAP11B in the RHO GTPase cycle. The gene has no measured role in small GTPase signalling, and a NOT annotation on the closely related GO:0043547 points the other way. Reason: Querying QuickGO by this reference returns 103 annotations over 103 distinct entities, all of them GO:0051056 by TAS - one term distributed across every participant in the pathway. So the row records that Reactome lists ARHGAP11B among RHO GTPase cycle participants, which it does because of the RhoGAP domain, not because anything was measured. Against that: the GAP activity is experimentally absent, GOA already carries NOT|involved_in GO:0043547 from primary literature, and the protein's measured activity is in the mitochondrial matrix. Keeping a regulation-of-small-GTPase-signalling term would leave the record asserting and denying the same biology in adjacent branches. Removed rather than demoted to non-core because there is no residual sense in which it is true. Propagation Review Root cause: PROPAGATION BAD Failure modes: PSEUDO OR SUBACTIVITY LOSS WRONG ORTHOLOG OR PARALOG Sources checked: Reactome:R-HSA-9012999 · Reactome pathway "RHO GTPase cycle" SUPPORTS SOURCE BUT NOT TARGET 103 entities receive GO:0051056 from this one reference by TAS. Membership in the pathway is asserted on domain content; for ARHGAP11B the domain is present and the function is not. UniProtKB:Q6P4F7 · human ARHGAP11A (the paralog ARHGAP11B was duplicated from) SUPPORTS SOURCE BUT NOT TARGET ARHGAP11A is a genuine participant in the RHO GTPase cycle and keeps this term. Listed here because WRONG_ORTHOLOG_OR_PARALOG is claimed above, and that failure mode should name the paralog whose biology is being transferred rather than be asserted bare. Supporting Evidence: PMID:27957544 However, contrary to ARHGAP11A (27, 28), ARHGAP11B does not exhibit RhoGAP activity when expressed in monkey fibroblast-like cells (23). |
| GO:2000179 positive regulation of neural precursor cell proliferation | IMP PMID:36098218 Human-specific ARHGAP11B ensures human-like basal progenitor... | NEW | Summary: Proposed new annotation capturing what ARHGAP11B actually does to neural progenitors, on the strength of the only loss-of-function evidence that exists for this gene and the only perturbation of it performed in human cells. Reason: Every GO:0021987 row in the current record is gain-of-function, and the necessity evidence produces no annotation anywhere. PMID:36098218 supplies it in both directions in human cerebral organoids: dominant-negative interference drops cycling basal progenitors to chimpanzee levels, and rescue of ARHGAP11A-plus-ARHGAP11B double-knockout human forebrain organoids shows that ARHGAP11B, but not ARHGAP11A, is required to maintain basal radial glia. The evidence code is IMP and the system is human, stated explicitly because the reverse mistake is easy to make on this gene: most of its literature is mouse, ferret or marmoset, and an experimental code on those results would assert a human experiment that was not done. This row is the exception, because the organoids are human. GO:2000179 is proposed as an addition rather than as a replacement for GO:0021987. Basal progenitors are nervous system progenitor cells and so fall under GO:0061351 neural precursor cell proliferation; the existing cerebral-cortex term remains true and is the right home for the tissue-level outcome, while this term names the cellular process being regulated and its direction. Supporting Evidence: PMID:36098218 Conversely, interference with ARHGAP11B's function in human cerebral organoids decreases basal progenitors down to the chimpanzee level. PMID:36098218 Moreover, ARHGAP11A or ARHGAP11B rescue experiments in ARHGAP11A plus ARHGAP11B double-knockout human forebrain organoids indicate that lack of ARHGAP11B, but not of ARHGAP11A, decreases the abundance of basal radial glia-the basal progenitor type thought to be of particular relevance for neocortex expansion. |
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Download this section (compressed HTML)Q: GOA currently ships a direct contradiction for ARHGAP11B: two IDA rows asserting NOT|enables GO:0005096 and one Reactome TAS row asserting enables GO:0005096, plus a Reactome TAS row for GO:0051056 that the NOT|involved_in GO:0043547 row contradicts. Should Reactome remove ARHGAP11B from the "RHOA GAPs" defined catalyst set of R-HSA-8981637 and from the RHO GTPase cycle participant list? And separately, should the GOA pipeline refuse to emit a positive annotation for a term that the same gene already carries as a curated NOT from experimental evidence? The second question generalises well beyond this gene.
Q: Does ARHGAP11B inhibit ANT-mediated adenine nucleotide transport, or does it inhibit mPTP opening without inhibiting transport? PMID:31883789 reports that pharmacological inhibition of ANT function mimics the ARHGAP11B effect, which suggests the former, but the cached record is abstract-only and the two claims are distinct. If transport inhibition is shown in the full text, GO:0141110 transporter inhibitor activity would be a better molecular function than the GO:0044325 transmembrane transporter binding proposed here.
Q: UniProt's Rho-GAP DOMAIN feature on ARHGAP11B is annotated as 49..250, which extends 30 residues past residue 220, the last position homologous to ARHGAP11A, and therefore into the human-specific frameshift C-terminus that is homologous to nothing. The effect is that the annotated domain on the inactive truncated paralog (202 aa) is longer than the annotated domain on the catalytically active parent ARHGAP11A (49..239, 191 aa). Should the ARHGAP11B feature be truncated at the end of homology, and should the interpro2go line from IPR000198 to GO:0007165 be gated on something other than a profile match for family members curated as inactive?
Q: Is there a GO-sanctioned way to state that a protein has retained a catalytic residue while losing the activity? ARHGAP11B keeps the canonical arginine finger at position 87 - UniProt annotates the Site, and it aligns reciprocally to both ARHGAP11A's and ARHGAP1's own annotated fingers - yet has no GAP activity. Pipelines and reviewers that gate catalytic terms on residue presence will get this gene wrong in the permissive direction.
Q: Should ARHGAP36 (Q6ZRI8) be re-examined? It is the reciprocal of ARHGAP11B within the same family: it has a threonine at its own UniProt-annotated arginine-finger position, yet UniProt asserts "GTPase activator for the Rho-type GTPases" for it on ECO:0000250, by similarity. Of the six reviewed human RhoGAP-profile proteins whose annotated finger is not an arginine, only OCRL carries an experimentally supported statement of catalytic inactivity; three are silent. So residue identity and curated activity are decoupled in both directions in this family, and a by-similarity activity claim over a substituted catalytic residue is the same class of defect this review corrects, pointing the other way.
Q: PAINT gave ARHGAP11B nothing - UniProt records zero PAN-GO annotations and GOA contains no IBA row for this gene - even though PANTHER places it in PTHR15670:SF4, a subfamily named "RHO GTPASE-ACTIVATING PROTEIN 11A" that it shares with its active paralog, which does receive GO:0005096 by IBA. That restraint is correct and is worth recording as a positive example: the paralog leak that PAINT avoided arrived through Reactome instead. Is the ARHGAP11B exclusion documented as a deliberate PAINT decision, so that a future re-run of the family does not reinstate it?
Q: Should the neurobehavioural phenotypes of ARHGAP11B-transgenic mice - increased memory flexibility and reduced anxiety (PMID:33938018) - support any annotation on the human gene product? They are several steps downstream of the molecular activity, were measured in mouse, and reflect an enlarged neocortex rather than a direct function, so no annotation is proposed here. But the same question recurs for every human-specific gene studied by transgenesis, and a consortium position would be useful.
Experiment: Reconstitute purified SLC25A4 or SLC25A5 into proteoliposomes and measure ADP/ATP exchange directly, with and without recombinant ARHGAP11B and with the ancestral 333-residue form as a specificity control. In parallel, measure calcium-retention capacity in mitochondria isolated from cells expressing wild-type ARHGAP11B, ancestral ARHGAP11B, and a matrix-targeting-deficient mutant. This separates three claims that the current record runs together - binds ANT, inhibits ANT transport, delays mPTP opening - and would decide between GO:0044325 and GO:0141110 as the molecular function.
Hypothesis: ARHGAP11B inhibits the adenine nucleotide translocase's transport activity, and that inhibition - not merely binding - is what delays mPTP opening.
Type: in vitro transport assay and isolated-mitochondria physiology
Experiment: Test a panel in human cerebral organoids or fetal neocortex ex vivo: full-length ARHGAP11B; the isolated 1-220 region, which is essentially ARHGAP11A's N-terminus; the ancestral 333-residue protein; and chimeras grafting residues 221-267 onto ARHGAP11A(1-220) and onto an unrelated matrix-targeted carrier. Score ANT co-immunoprecipitation, calcium retention capacity and basal progenitor abundance. PMID:27957544 showed that both the loss of GAP activity and the gain of the novel C-terminus are needed, but which of the two supplies the ANT interaction has not been resolved, and that is the difference between a neomorphic binding module and a simple loss-of-function.
Hypothesis: The human-specific C-terminus (residues 221-267), not the loss of GAP activity as such, is the part of ARHGAP11B that binds ANT and confers the mitochondrial function.
Type: structure-function mapping in human progenitors
Experiment: Apply the ARHGAP11A220 dominant-negative, and separately an ARHGAP11B-specific knockdown designed against the human-specific 3-prime sequence so that ARHGAP11A is untouched, to human fetal neocortical tissue in organotypic slice culture, and quantify cycling basal progenitors and basal radial glia. The only loss-of-function evidence for this gene is in organoids (PMID:36098218) plus one dominant-negative experiment in fetal tissue reported within PMID:31883789; a clean, ARHGAP11B-specific knockdown in primary human tissue would convert the proposed GO:2000179 IMP from a single-system result into a robust one.
Hypothesis: ARHGAP11B is required for normal basal progenitor levels in primary human fetal neocortex, not only in organoids.
Type: loss-of-function in primary human tissue
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