Gene Ontology annotation through association of InterPro records with GO terms
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion.
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ARHGAP11B arose by partial duplication of ARHGAP11A on the human lineage after the split from chimpanzee, and when expressed in embryonic mouse neocortex promotes basal progenitor generation and self-renewal and can induce gyrification.
"ARHGAP11B arose from partial duplication of ARHGAP11A (which encodes a Rho guanosine triphosphatase-activating protein) on the human lineage after separation from the chimpanzee lineage. Expression of ARHGAP11B in embryonic mouse neocortex promotes basal progenitor generation and self-renewal and can increase cortical plate area and induce gyrification."
A single splice site mutation in human-specific ARHGAP11B causes basal progenitor amplification.
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A single C-to-G substitution creates a novel splice donor site; the resulting frameshift truncates the GAP domain and appends a 47-residue human-specific C-terminus beginning at residue 221.
"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"
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Modern ARHGAP11B has no RhoGAP activity in intact cells; the reconstructed ancestral protein, which has a complete GAP domain, does have RhoGAP activity but cannot amplify basal progenitors. Activity and progenitor amplification are anti-correlated across the three proteins tested.
"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)."
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The first 220 residues of ARHGAP11B are 98% identical to ARHGAP11A and encompass most of the GAP domain, which ARHGAP11A places at residues 46 to 246.
"The first 220 amino acids of ARHGAP11B are 98% identical to those of ARHGAP11A (216 of 220 residues; for a discussion of the four amino acid changes, see below and the Supplementary Materials) and encompass most of its GAP domain (amino acids 46 to 246)"
Human-Specific ARHGAP11B Acts in Mitochondria to Expand Neocortical Progenitors by Glutaminolysis.
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ARHGAP11B is imported into mitochondria, interacts with the adenine nucleotide translocase, and inhibits the mitochondrial permeability transition pore.
"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)."
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Basal progenitor expansion by ARHGAP11B requires its presence in mitochondria and requires glutaminolysis, and is mimicked by pharmacological inhibition of ANT function or of mPTP opening.
"BP expansion by ARHGAP11B requires its presence in mitochondria, and pharmacological inhibition of ANT function or mPTP opening mimic BP expansion by ARHGAP11B."
Expression of human-specific ARHGAP11B in mice leads to neocortex expansion and increased memory flexibility.
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A transgenic mouse line expressing ARHGAP11B at physiological levels has an enlarged neocortex with more upper-layer neurons that persists into adulthood.
"Here, we generated a transgenic mouse line with physiological ARHGAP11B expression that exhibits increased neocortical size and upper-layer neuron numbers persisting into adulthood."
Human-specific ARHGAP11B induces hallmarks of neocortical expansion in developing ferret neocortex.
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In the gyrencephalic ferret, ARHGAP11B expression markedly increases proliferative basal radial glia, extends the neurogenic period and increases upper-layer neurons, extending the progenitor phenotype beyond the lissencephalic mouse.
"In contrast to its effects in mouse, ARHGAP11B markedly increases proliferative basal radial glia, a progenitor cell type thought to be instrumental for neocortical expansion, and results in extension of the neurogenic period and an increase in upper-layer neurons."
Human-specific ARHGAP11B increases size and folding of primate neocortex in the fetal marmoset.
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Expressed under its own human promoter in fetal marmoset neocortex, ARHGAP11B increases basal radial glia in the outer subventricular zone and upper-layer neurons, enlarges the neocortex and induces folding, extending the phenotype to a non-human primate.
"ARHGAP11B expressed in fetal neocortex of the common marmoset under control of the gene's own (human) promoter increased the numbers of basal radial glia progenitors in the marmoset outer subventricular zone, increased the numbers of upper-layer neurons, enlarged the neocortex, and induced its folding."
Human-specific ARHGAP11B ensures human-like basal progenitor levels in hominid cerebral organoids.
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The only study that perturbs ARHGAP11B in a human system, and it does so in both directions: dominant-negative interference in human cerebral organoids drops basal progenitors to chimpanzee levels, while expression in chimpanzee organoids doubles them.
"Conversely, interference with ARHGAP11B's function in human cerebral organoids decreases basal progenitors down to the chimpanzee level."
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Rescue of ARHGAP11A-plus-ARHGAP11B double-knockout human forebrain organoids shows that ARHGAP11B, but not ARHGAP11A, is required to maintain basal radial glia, so the requirement is specific to the human-specific paralog.
"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."
The evolution and population diversity of human-specific segmental duplications.
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Places ARHGAP11B among the ten human-specific segmental duplication families whose copy number never returns to the ancestral state, with evidence of mRNA splicing and no common gene-disruptive mutations in the general population.
"we highlight ten gene families (e.g., ARHGAP11B and SRGAP2C) where copy number never returns to the ancestral state, there is evidence of mRNA splicing, and no common gene-disruptive mutations are observed in the general population."
RHOA GAPs stimulate RHOA GTPase activity
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This Reactome reaction has a single set-level catalyst, "GTPase activator activity of RHOA GAPs [cytosol]". Querying QuickGO by this reference returns 43 annotations over 22 distinct entities (numberOfHits 43, all 43 read on one page), of which 21 entities receive GO:0005096 and 21 receive GO:0005829, every one by TAS. It is a bulk projection over a defined catalyst set, not a judgement about any individual member.
RHO GTPase cycle
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Querying QuickGO by this reference returns 103 annotations over 103 distinct entities (numberOfHits 103, all 103 read across two pages), all of them GO:0051056 by TAS. It is a pathway-membership projection distributed across every participant.
ARHGAP11B: a GAP-dead RhoGAP that still has its arginine finger
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ARHGAP11B is colinear with ARHGAP11A through residue 220 and diverges after that point.
"**Derived divergence point: residue 220.**"
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ARHGAP11B retains the canonical arginine finger despite being experimentally GAP-dead.
"So the residue test that normally exposes a pseudo-enzyme returns *retained* here, for a protein that two independent experimental annotations record as GAP-dead."
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The frameshift removes only a small measured subset of mapped GAP:GTPase interface positions.
"The truncation therefore removes 2 of 24 mapped GAP:GTPase interface positions (8%) while leaving the arginine finger in place."
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UniProt's Rho-GAP DOMAIN feature continues into ARHGAP11B's human-specific frameshifted C-terminus.
"UniProt's Rho-GAP DOMAIN feature on ARHGAP11B runs 30 residues past the last residue that is homologous to ARHGAP11A"