A0A6I8TLE4

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

A0A6I8TLE4 is a predicted Ras GTPase-activating protein (RasGAP) in Aedes aegypti, classified by PANTHER as an ortholog of the Drosophila raskol gene (PTHR10194:SF60). The protein is 1442 amino acids and contains a conserved multi-domain architecture characteristic of the DAB2IP/SynGAP-like RasGAP subfamily: a RasGAP catalytic domain (IPR001936), a C2 domain (IPR000008, SynGAP-like subtype per CDD cd04013), a PH domain (IPR001849, SynGAP-like subtype per CDD cd13262), and a DAB2P C-terminal domain (IPR021887). The RasGAP domain catalyzes stimulation of the intrinsic GTPase activity of Ras-family small GTPases, converting them from the active GTP-bound state to the inactive GDP-bound state, thereby functioning as a negative regulator of Ras signaling. The C2 and PH domains are predicted to mediate calcium-dependent and phosphoinositide-dependent membrane targeting, respectively, enabling recruitment to specific membrane compartments where Ras signaling occurs. The DAB2P_C domain is associated with scaffold/adaptor functions in related proteins such as human DAB2IP. No direct experimental characterization of this specific gene product has been published; functional annotation is based on conserved domain architecture, PANTHER subfamily classification, and orthology to characterized RasGAPs.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005096 GTPase activator activity
ISS
GO_REF:0000002 		NEW
Summary: Proposed new annotation based on conserved RasGAP domain (IPR001936, Pfam PF00616), the RasGAP catalytic signature motif (PROSITE PS00509), PANTHER subfamily classification as raskol (PTHR10194:SF60), and CDD match to RasGAP_DAB2IP (cd05136). GTPase activator activity is the canonical function of the RasGAP domain, which stimulates the intrinsic GTPase activity of Ras-family small GTPases. This is also predicted by UniProt keyword mapping (IEA:UniProtKB-KW) and by ProtNLM2.
Reason: Strong domain-based evidence from multiple independent sources (InterPro, CDD, PANTHER, PROSITE, Pfam) all converge on RasGAP function. The RasGAP domain is well-characterized with high predictive value for GTPase activator activity.
GO:0007265 Ras protein signal transduction
ISS
GO_REF:0000002 		NEW
Summary: Proposed new annotation. Ras protein signal transduction is the direct biological process context for RasGAP activity. The protein's domain architecture (RasGAP + C2 + PH) is specific to Ras signaling regulators, and the PANTHER classification places it in the RasGAP family (PTHR10194).
Reason: RasGAP domain-containing proteins are by definition participants in Ras protein signal transduction. This is the direct process annotation corresponding to the molecular function.
GO:0046580 negative regulation of Ras protein signal transduction
ISS
GO_REF:0000002 		NEW
Summary: Proposed new annotation. RasGAPs are negative regulators of Ras signaling because they accelerate GTP hydrolysis, converting active GTP-Ras to inactive GDP-Ras. This regulatory directionality is inherent to the GAP mechanism.
Reason: The GAP mechanism is inherently inhibitory toward Ras signaling. All characterized RasGAP domain proteins function as negative regulators.
GO:0005829 cytosol
ISS
GO_REF:0000002 		NEW
Summary: Proposed new annotation. RasGAP family proteins are typically cytosolic proteins that are recruited to membranes upon signaling. The deep research report predicts cytosolic localization based on domain architecture analysis.
Reason: Cytosol is the default localization for soluble RasGAP proteins before membrane recruitment. Supported by domain architecture inference from the deep research report.
GO:0005886 plasma membrane
ISS
GO_REF:0000002 		NEW
Summary: Proposed new annotation. The C2 and PH domains predict membrane targeting. Ras GTPases are predominantly plasma membrane-associated, and their GAPs must localize to the plasma membrane to exert their regulatory function. The SynGAP-like C2 domain (CDD cd04013) and PH domain (CDD cd13262) are specifically associated with membrane-targeting in this protein family.
Reason: C2 and PH domains are well-established membrane-targeting modules. RasGAP function requires co-localization with membrane-anchored Ras GTPases at the plasma membrane.

Core Functions

Predicted Ras GTPase-activating protein that stimulates the intrinsic GTPase activity of Ras-family small GTPases, accelerating hydrolysis of GTP to GDP and thereby inactivating Ras signaling. This is the canonical function of all RasGAP domain-containing proteins and is strongly supported by the conserved RasGAP domain (IPR001936, Pfam PF00616), the RasGAP catalytic signature (PROSITE PS00509), and the PANTHER subfamily assignment to raskol (PTHR10194:SF60). The CDD match to cd05136 (RasGAP_DAB2IP) further specifies this as a DAB2IP-subfamily RasGAP.

Molecular Function:
GTPase activator activity
Directly Involved In:
Ras protein signal transduction negative regulation of Ras protein signal transduction
Cellular Locations:
cytosol plasma membrane
Supporting Evidence:
  • file:AEDAE/A0A6I8TLE4/A0A6I8TLE4-deep-research-falcon.md
    domain-based annotation indicating C2, PH, Ras GTPase, and DAB2P_C-related features

References

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Suggested Questions for Experts

Q: Is A0A6I8TLE4 the true ortholog of Drosophila raskol, and does it share the same developmental and signaling roles in Aedes aegypti? PANTHER classifies it as PTHR10194:SF60 (RAS GTPASE-ACTIVATING PROTEIN RASKOL) but direct orthology confirmation via synteny or phylogenetic analysis would be valuable.

Q: What are the specific Ras-family substrates of this protein? DAB2IP-type RasGAPs can act on H-Ras, R-Ras, and Rap1 with different specificities. The CDD match to RasGAP_DAB2IP (cd05136) suggests potential activity toward multiple Ras-family members.

Q: Does this protein play a role in vector competence or innate immunity in Aedes aegypti? Ras signaling pathways are implicated in mosquito immune responses to arboviruses and Plasmodium parasites.

Suggested Experiments

Experiment: Express and purify the RasGAP domain of A0A6I8TLE4 and test GAP activity in vitro using a GTPase assay (e.g., malachite green phosphate release assay) with recombinant H-Ras, K-Ras, R-Ras, and Rap1 as substrates. Compare catalytic efficiency to known RasGAPs.

Hypothesis: A0A6I8TLE4 has GTPase activator activity toward Ras-family GTPases.

Type: biochemical assay

Experiment: Generate a GFP-tagged A0A6I8TLE4 construct and express in Aedes aegypti Aag2 cells. Assess subcellular localization by confocal microscopy under basal conditions and after stimulation with growth factors or calcium ionophore to test stimulus-dependent membrane recruitment.

Hypothesis: A0A6I8TLE4 localizes to the plasma membrane via its C2 and PH 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

The RasGAP domain and conserved-site assignments support GTPase activation. The same molecular function is already recorded in UniProt.

Source documents: genes/AEDAE/A0A6I8TLE4/A0A6I8TLE4-uniprot.txt · genes/AEDAE/A0A6I8TLE4/A0A6I8TLE4-goa.tsv · publications/PMID_12787671.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
CNN — Correct but not novel Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt 2024_06 pilot
Review rationale: The target contains a RasGAP domain and the RasGAP conserved-site signature, alongside PH and C2 domains. Mutational analysis of characterized RasGAPs establishes that conserved RasGAP elements stimulate GTP hydrolysis by the bound GTPase (PMID:12787671); this supports transfer of the broad GTPase activator activity to the target without specifying a substrate beyond the available evidence. The exact GO term is present in the cached UniProt record, although the local GOA export is empty. Correctness rests on the domain and mechanistic evidence, while the existing annotation establishes overlap only.
Supporting Evidence:
  • file:AEDAE/A0A6I8TLE4/A0A6I8TLE4-uniprot.txt: "ID A0A6I8TLE4_AEDAE Unreviewed; 1442 AA. ... DR GO; GO:0005096; F:GTPase activator activity; IEA:UniProtKB-KW. ... DR InterPro; IPR023152; RasGAP_CS. ... DR InterPro; IPR001936; RasGAP_dom. ... DR PANTHER; PTHR10194:SF60; RAS GTPASE-ACTIVATING PROTEIN RASKOL; 1."
  • PMID:12787671: "The finger loop is crucial for the stabilization of the transition state"

Deep Research

Falcon

(A0A6I8TLE4-deep-research-falcon.md)

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