A0A6I8TLE4

UniProt ID: A0A6I8TLE4
Organism: Aedes aegypti
Review Status: DRAFT
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Gene Description

A0A6I8TLE4 is the 1442-residue AAEL019982-PE splice product of Aedes aegypti gene AAEL019982 (NCBI Gene 5579847), one of five UniProt products of this gene that differ only in their first ~130 residues. It is the mosquito ortholog of Drosophila raskol, sharing PANTHER subfamily PTHR10194:SF60 and 61% sequence identity with it, and belongs to the DAB2IP/RASAL2/SynGAP-like branch of the Ras GTPase-activating protein family. The protein has an N-terminal SynGAP-like PH domain, a C2 domain, a central RasGAP domain that retains the catalytic arginine finger (R483, in a TFRGNS finger loop identical to raskol and neurofibromin), a long disordered middle region, and a C-terminal DAB2IP-type (DAB2P_C) region. By homology it is expected to accelerate GTP hydrolysis by a Ras-subfamily small GTPase and so to damp Ras-type signalling; its substrate has not been identified. The Drosophila ortholog localises to the plasma membrane and apical cell cortex of epithelial cells, colocalises with E-cadherin at cell-cell contacts and is needed for border-cell adhesion and actin-protrusion control. The mosquito protein itself has not been studied experimentally.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005096 GTPase activator activity
ISS
file:AEDAE/A0A6I8TLE4/A0A6I8TLE4-bioinformatics/RESULTS-rereview.md 		NEW
Summary: Proposed annotation (GOA holds no rows for this accession). The protein has a complete RasGAP domain (IPR001936, 391-735) with the conserved site and retains the catalytic arginine finger (R483, TFRGNS). GTPase activator activity is the IBD assertion PAINT placed at the PTHR10194 root node PTN008939999, from which A0A6I8TLE4 descends, and within its own subfamily SF60 purified BUD2 stimulates GTP hydrolysis by its Ras-like target and gap-2 complements a fission yeast RasGAP mutant.
Reason: Family-wide catalytic function with an intact catalytic interface in the target. Kept at the general GTPase activator level because the substrate GTPase is not known for this protein or for raskol, and SF60 members target different Ras-subfamily GTPases.
Supporting Evidence:
file:AEDAE/A0A6I8TLE4/A0A6I8TLE4-bioinformatics/RESULTS-rereview.md
The catalytic arginine finger of the RasGAP domain is conserved in A0A6I8TLE4.
PMID:8371782
Bud2p purified from yeast stimulates GTP hydrolysis by Bud1p
PMID:9619631
C. elegans gap-2 encodes a novel Ras-GAP
GO:1902531 regulation of intracellular signal transduction
ISS
file:AEDAE/A0A6I8TLE4/A0A6I8TLE4-bioinformatics/RESULTS-rereview.md 		NEW
Summary: Proposed annotation replacing the earlier proposals of GO:0007265 Ras protein signal transduction and GO:0046580 negative regulation of Ras protein signal transduction. This is the process term PAINT placed at the PTHR10194 root node alongside GTPase activator activity, and the term raskol, gap-2 and BUD2 carry by IBA. A GAP acts on the GTPase of a signalling cassette rather than relaying the signal, so GO:0007265 was the wrong relation; and although one of the node's seeds, human DAB2IP (Q5VWQ8), has an experimental (IMP) annotation to GO:0046580, PAINT curators propagated only the general regulation term, which is treated here as a deliberate decision given the varied substrates within the family.
Reason: Follows the PAINT node placement and the conserved catalytic domain. A more specific Ras-pathway term would need evidence on the substrate GTPase for this branch.
Supporting Evidence:
PMID:9619631
GAP-2 appears to function as a negative regulator of LET-60 Ras during larval development
file:AEDAE/A0A6I8TLE4/A0A6I8TLE4-bioinformatics/RESULTS-rereview.md
Drosophila raskol is by far the closest relative and shares the PANTHER subfamily, so it is the dipteran ortholog.
GO:0005886 plasma membrane
ISS
PMID:30763317
Evolutionary rate covariation analysis of E-cadherin identif... 		NEW
Summary: Proposed annotation by transfer from the Drosophila ortholog raskol (same PANTHER subfamily SF60, 61% identity), which localises to the cell membrane and apical surface of epithelial cells and colocalises with DE-cadherin at cell contacts. The target has the same SynGAP-like PH and C2 membrane-binding modules. The earlier proposal of cytosol was withdrawn: no evidence placed the ortholog in the cytosol rather than at the membrane and cortex.
Reason: Ortholog localisation, consistent with the conserved PH and C2 domains. Placed outside core function because it rests on a single ortholog study.
Supporting Evidence:
PMID:30763317
In Drosophila stage 8 embryos, before BCs have delaminated, Raskol localized to the cell membrane of BCs and PCs and was enriched at the PC apical membrane

Core Functions

Ras-family GTPase-activating protein of the raskol/DAB2IP-like branch. Its RasGAP domain, with a conserved catalytic arginine finger, is expected to accelerate GTP hydrolysis by a Ras-subfamily small GTPase and thereby limit Ras-type intracellular signalling; the substrate GTPase has not been identified.

Molecular Function:
GTPase activator activity
Directly Involved In:
regulation of intracellular signal transduction
Cellular Locations:
plasma membrane
Supporting Evidence:
  • file:AEDAE/A0A6I8TLE4/A0A6I8TLE4-bioinformatics/RESULTS-rereview.md
    The catalytic arginine finger of the RasGAP domain is conserved in A0A6I8TLE4.
  • PMID:8371782
    Bud2p purified from yeast stimulates GTP hydrolysis by Bud1p
  • PMID:30763317
    In Drosophila stage 8 embryos, before BCs have delaminated, Raskol localized to the cell membrane of BCs and PCs and was enriched at the PC apical membrane

References

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Suggested Questions for Experts

Q: Which small GTPase does the raskol branch act on? Human DAB2IP and RASAL2 act on Ras and SynGAP on Ras and Rap, yeast BUD2 on the Rap-like Rsr1, and C. elegans gap-2 genetically on LET-60 Ras. If insect raskol is a Ras GAP, GO:0046580 negative regulation of Ras protein signal transduction would be justified for the branch; PAINT currently assigns only GO:1902531 at the family root.

Q: Do the five AAEL019982 products, which differ only in their first ~130 residues (partly within the broad PH-domain region), differ in membrane targeting or tissue expression?

Q: Does the mosquito protein, like Drosophila raskol, colocalise with E-cadherin at adherens junctions?

Suggested Experiments

Experiment: Purify the RasGAP domain (wild type and R483A) and measure single-turnover GTP hydrolysis by recombinant A. aegypti Ras, Rap1 and R-Ras homologs (phosphate-release or fluorescent-nucleotide assays).

Hypothesis: The RasGAP domain of A0A6I8TLE4 stimulates GTP hydrolysis by a mosquito Ras-subfamily GTPase, and the R483A arginine-finger mutation abolishes it.

Type: biochemical assay

Experiment: Express tagged full-length protein and PH/C2 deletion variants in Aag2 cells and score cortical versus cytosolic localisation and colocalisation with E-cadherin.

Hypothesis: A0A6I8TLE4 localises to the plasma membrane and cell contacts through its PH and C2 domains.

Type: cell biology / microscopy

External Prediction Reviews

These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.

ProtNLM2 External predictions

View prediction review YAML · A0A6I8TLE4-protnlm-predictions-review.yaml · Review status: COMPLETE

A0A6I8TLE4 is an AAEL019982 splice product and the mosquito ortholog of Drosophila raskol (PANTHER PTHR10194:SF60), with a complete RasGAP domain that retains the catalytic arginine finger. The single ProtNLM2 GO prediction, GTPase activator activity, is supported by the PAINT IBD at the PTHR10194 root node and by biochemical GAP activity of an SF60 relative. GOA holds no annotation for this accession or for any of the other four AAEL019982 products, so the prediction is novel.

Source documents: genes/AEDAE/A0A6I8TLE4/A0A6I8TLE4-uniprot.txt · genes/AEDAE/A0A6I8TLE4/A0A6I8TLE4-goa.tsv · genes/AEDAE/A0A6I8TLE4/A0A6I8TLE4-ai-review.yaml · genes/AEDAE/A0A6I8TLE4/A0A6I8TLE4-bioinformatics/RESULTS-rereview.md · interpro/panther/PTHR10194/PTHR10194-review.yaml · interpro/panther/PTHR10194/PTHR10194-paint.tsv · publications/PMID_12787671.md · publications/PMID_8371782.md

Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.

GO:0005096 GTPase activator activity GO_MF
COR — Correct novel prediction Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt 2024_06 pilot
Review rationale: The target has a complete RasGAP domain (IPR001936) with the RasGAP conserved site and keeps the catalytic arginine finger (R483 in a TFRGNS loop identical to raskol and matching neurofibromin). Mutational work on neurofibromin and p120GAP shows that the finger loop stabilises the GTP-hydrolysis transition state (PMID:12787671). PAINT placed GTPase activator activity as an IBD at the PTHR10194 root node PTN008939999, from which this protein descends, and within subfamily SF60 purified yeast Bud2p stimulates GTP hydrolysis by its Ras-like target (PMID:8371782). This is a phylogenetic and mechanistic inference; the mosquito protein has not been assayed, and the general term is appropriate because the substrate GTPase is unknown. The re-reviewed gene review proposes the same term as a NEW core function. QuickGO returns no annotation for A0A6I8TLE4 or the other AAEL019982 products, and the UniProt keyword-derived GO line is not in GOA, so the prediction is novel.
Supporting Evidence:

Deep Research

Falcon

(A0A6I8TLE4-deep-research-falcon.md)

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📚 Additional Documentation

Notes

(A0A6I8TLE4-notes.md)

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📄 View Raw YAML

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