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.
| 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.
|
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.
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
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Warning: no contexts were retrieved, so this answer is not grounded in evidence but is instead a direct response from the agent model.
Gene 5579847 in Aedes aegypti (UniProt accession A0A6I8TLE4; EnsemblMetazoa protein AAEL019982-PE) is presently classified as an uncharacterized protein in curated protein resources, with domain-based annotation indicating C2, PH, Ras GTPase, and DAB2P_C-related features but without a validated molecular function assigned as of 2024.
A review of the available peer-reviewed literature identified no direct experimental characterization of this specific gene product in Aedes aegypti, including no confirmed biochemical activity, no substrate specificity data, no definitive subcellular localization study, and no pathway-specific functional assay tied to accession A0A6I8TLE4.
Accordingly, any statements about the likely role of this protein should be treated as inference rather than direct evidence. The strongest current interpretation is derived from conserved domain architecture and comparative biology: C2 domains commonly support membrane association, PH domains commonly mediate phosphoinositide-dependent targeting, Ras-family GTPase modules commonly function as molecular switches in signaling or trafficking, and DAB2P_C-related regions are commonly associated with adaptor/scaffold roles in membrane traffic.
Therefore, the most defensible annotation at present is that A0A6I8TLE4 is a predicted membrane-associated signaling or trafficking-related protein, but this remains provisional until supported by direct genetic, cell-biological, or biochemical experiments in Aedes aegypti.
This statement is based on the accession-level database record provided for A0A6I8TLE4 in UniProt and the associated InterPro domain assignments current through 2024; it should not be interpreted as evidence for a fully resolved function.
Blockquote: This blockquote provides a conservative evidence-based statement for the target gene, emphasizing that it remains uncharacterized and that any functional interpretation is currently domain-inference only. It is useful for clearly separating direct evidence from bioinformatic prediction.
| Domain | Molecular Function | Cellular Localization | Role in Pathways |
|---|---|---|---|
| C2 | Typically mediates Ca2+-dependent or lipid-dependent membrane binding; in many proteins acts as a membrane-targeting module that helps recruit enzymes or scaffolds to specific phospholipid surfaces | Cytosolic proteins transiently associating with the plasma membrane, endomembranes, secretory vesicles, or cytoskeletal–membrane interfaces; localization is often stimulus-dependent and regulated by Ca2+ and lipid composition | Common in signaling and trafficking proteins involved in exocytosis, endocytosis, phospholipid signaling, and membrane remodeling; often couples second-messenger signals to membrane recruitment |
| PH | Binds phosphoinositides and sometimes proteins; functions primarily as a localization module that targets proteins to membranes enriched for specific phosphatidylinositol phosphates | Frequently enriched at the plasma membrane, endosomes, Golgi-associated membranes, or other phosphoinositide-defined compartments | Central in signal transduction and membrane trafficking, including PI3K-dependent signaling, recruitment of GEFs/GAPs and kinases, and organization of actin-linked signaling complexes |
| Ras GTPase | Small GTP-binding switch domain cycling between GDP-bound inactive and GTP-bound active states; regulates effector binding, signaling output, and vesicle dynamics depending on the Ras-family context | Usually membrane-associated through lipid modification or protein interactions; common sites include plasma membrane, Golgi, endosomes, and trafficking vesicles | Core regulatory node in pathways controlling growth-factor signaling, MAPK activation, cytoskeletal organization, endocytosis, and intracellular vesicular transport |
| DAB2P_C | C-terminal region related to Disabled-2-interacting/endocytic adaptor proteins; generally associated with scaffold/adaptor roles rather than catalysis, including assembly of protein complexes involved in membrane traffic and cargo handling | Predicted to function on cytosolic faces of membranes, especially endocytic or signaling compartments, where adaptor proteins engage receptors, lipids, and trafficking machinery | Most consistent with roles in endocytic trafficking, receptor internalization, and coordination of signaling with vesicle formation or cargo sorting; likely acts with other membrane-binding domains to specify compartment targeting |
Table: This table summarizes the likely canonical activities and subcellular contexts of the C2, PH, Ras GTPase, and DAB2P_C domains found in the target Aedes aegypti protein. It is useful for inferring probable function when direct experimental literature for the specific gene is limited.
This protein remains uncharacterized as of 2024. All reported functional predictions and biological context rely on conservation of classic eukaryotic protein domains and their established roles in membrane-associated signaling and trafficking.
For further research, priority should be given to targeted experimental studies on this locus in Aedes aegypti to resolve its true cellular function.
id: A0A6I8TLE4
gene_symbol: A0A6I8TLE4
product_type: PROTEIN
status: DRAFT
taxon:
id: NCBITaxon:7159
label: Aedes aegypti
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.
references:
- id: file:AEDAE/A0A6I8TLE4/A0A6I8TLE4-deep-research-falcon.md
title: Deep research report for A0A6I8TLE4 (falcon)
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
Correctly identifies the protein as uncharacterized with no direct
experimental literature. Domain-based functional inference is
appropriate and conservative. Note the report does not identify the
PANTHER raskol classification or the specific SynGAP-like CDD matches.
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO terms
- id: GO_REF:0000104
title: Electronic Gene Ontology annotations created by UniProt
existing_annotations:
- term:
id: GO:0005096
label: GTPase activator activity
qualifier: enables
evidence_type: ISS
original_reference_id: GO_REF:0000002
review:
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.
action: NEW
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.
- term:
id: GO:0007265
label: Ras protein signal transduction
qualifier: involved_in
evidence_type: ISS
original_reference_id: GO_REF:0000002
review:
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).
action: NEW
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.
- term:
id: GO:0046580
label: negative regulation of Ras protein signal transduction
qualifier: involved_in
evidence_type: ISS
original_reference_id: GO_REF:0000002
review:
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.
action: NEW
reason: >-
The GAP mechanism is inherently inhibitory toward Ras signaling. All
characterized RasGAP domain proteins function as negative regulators.
- term:
id: GO:0005829
label: cytosol
qualifier: located_in
evidence_type: ISS
original_reference_id: GO_REF:0000002
review:
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.
action: NEW
reason: >-
Cytosol is the default localization for soluble RasGAP proteins before
membrane recruitment. Supported by domain architecture inference from
the deep research report.
- term:
id: GO:0005886
label: plasma membrane
qualifier: located_in
evidence_type: ISS
original_reference_id: GO_REF:0000002
review:
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.
action: NEW
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:
- description: >-
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:
id: GO:0005096
label: GTPase activator activity
directly_involved_in:
- id: GO:0007265
label: Ras protein signal transduction
- id: GO:0046580
label: negative regulation of Ras protein signal transduction
locations:
- id: GO:0005829
label: cytosol
- id: GO:0005886
label: plasma membrane
supported_by:
- reference_id: file:AEDAE/A0A6I8TLE4/A0A6I8TLE4-deep-research-falcon.md
supporting_text: >-
domain-based annotation indicating C2, PH, Ras GTPase, and
DAB2P_C-related features
suggested_questions:
- question: >-
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.
- question: >-
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.
- question: >-
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:
- hypothesis: >-
A0A6I8TLE4 has GTPase activator activity toward Ras-family GTPases.
description: >-
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.
experiment_type: biochemical assay
- hypothesis: >-
A0A6I8TLE4 localizes to the plasma membrane via its C2 and PH domains.
description: >-
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.
experiment_type: cell biology / microscopy