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Now that I have reviewed the model and gathered the necessary information, I'll provide a detailed evaluation of GO-CAM model 646ff70100000611.

Review of GO-CAM Model: gomodel:646ff70100000611

Overview

Title: Ubiquitination of RagA/RRAGA by RNF152 inhibits the mTORC1 signaling (Human)

Taxon: Human (NCBITaxon:9606)

Status: Production

This GO-CAM model describes a signaling pathway in which the E3 ubiquitin ligase RNF152 ubiquitinates RagA/RRAGA to negatively regulate mTORC1 signaling. The model represents a complex regulatory mechanism that occurs on the lysosomal membrane.

Diagram of the Model

The model consists of four main activities: 1. RagA/RRAGA GTP binding activity 2. RagA/RRAGA protein-membrane adaptor activity 3. RNF152 ubiquitin-protein ligase activity 4. GATOR1 complex GTPase activator activity

The causal relationships show: - RagA/RRAGA GTP binding directly positively regulates RagA/RRAGA protein-membrane adaptor activity - RNF152 ubiquitin-protein ligase activity directly positively regulates GATOR1 complex GTPase activator activity - GATOR1 complex GTPase activator activity directly negatively regulates RagA/RRAGA GTP binding activity

Evaluation of the Model Components

1. RagA/RRAGA activities:

The model accurately represents two activities of RagA/RRAGA: - GTP binding (GO:0005525): This is correctly located at the lysosomal membrane (GO:0005765) and is part of the positive regulation of TORC1 signaling (GO:1904263). - Protein-membrane adaptor activity (GO:0043495): This is also correctly located at the lysosomal membrane and is part of protein localization to lysosome (GO:0061462).

The causal relationship between these activities (RO:0002629 - "directly positively regulates") is biologically accurate, as GTP binding by RagA enables its function as a membrane adaptor that helps recruit mTORC1 to the lysosomal surface.

2. RNF152 activity:

  • Ubiquitin protein ligase activity (GO:0061630): This is correctly located at the lysosomal membrane and is part of protein K63-linked ubiquitination (GO:0070534).

The literature evidence (PMID:25936802) supports that RNF152 is a lysosome-localized E3 ubiquitin ligase that promotes K63-linked polyubiquitination of RagA.

3. GATOR1 complex activity:

  • GTPase activator activity (GO:0005096): This is correctly located at the lysosomal membrane and is part of the negative regulation of TORC1 signaling (GO:1904262).

The literature evidence (PMID:29590090) supports that GATOR1 functions as a GAP for RagA, stimulating its GTPase activity.

4. Causal relationships:

The model accurately represents that: - RNF152 ubiquitin ligase activity positively regulates GATOR1 GAP activity (RO:0002629) - GATOR1 GAP activity negatively regulates RagA GTP binding (RO:0002630)

These relationships are supported by the evidence that ubiquitination of RagA by RNF152 promotes the recruitment of GATOR1, which then stimulates GTP hydrolysis by RagA, converting it to its inactive GDP-bound state.

Comparison with Literature Evidence

The model is consistent with the cited literature:

  1. PMID:31601764 and PMID:31601708 demonstrate that RagA binds GTP and functions in mTORC1 recruitment to lysosomes through protein-membrane adaptor activity.

  2. PMID:25936802 establishes that:

  3. RNF152 targets RagA for K63-linked polyubiquitination
  4. This ubiquitination occurs at four lysine residues (K142, K220, K230, K244)
  5. Ubiquitination promotes the binding of GATOR1 to RagA

  6. This process inhibits mTORC1 activation

  7. PMID:29590090 confirms that GATOR1:

  8. Functions as a GAP for RagA
  9. Stimulates GTP hydrolysis by RagA
  10. Negatively regulates mTORC1 signaling

Quality Assessment

Strengths:

  1. Completeness: The model captures the key molecular activities and causal relationships described in the literature.
  2. Evidence: All components are supported by appropriate literature evidence.
  3. Cellular location: The lysosomal membrane localization is consistently represented for all activities.
  4. Biological process context: Relevant biological processes (mTORC1 signaling, ubiquitination) are incorporated appropriately.

Potential Improvements:

  1. Complex representation: The model uses GO:1990130 (GATOR1 complex) as the enabler of the GTPase activator activity, which is appropriate according to the GO-CAM guidelines for complexes when the specific subunit carrying the activity is not explicitly known. However, the model could potentially be expanded to include the specific subunits of GATOR1 (DEPDC5, NPRL2, and NPRL3) if their specific roles in GAP activity were to be annotated.

  2. Additional regulatory components: The model could potentially be expanded to include:

  3. The role of amino acid sensing in regulating RNF152-RagA interaction
  4. The involvement of deubiquitinating enzymes (like DUB3 mentioned in PMID:25936802)

  5. The interaction with the Ragulator complex

  6. RagC representation: The model focuses on RagA, but RagA functions as a heterodimer with RagC. The model could potentially include RagC's role, particularly as RagA-RagC heterodimer nucleotide states are critical for mTORC1 regulation.

Compliance with GO-CAM Best Practices

The model follows the GO-CAM best practices for complex annotation. As described in the document "How to annotate complexes in GO-CAM": - When the subunit carrying the molecular activity is not known, using the GO accession for the complex (as done for GATOR1 in this model) is appropriate.

Conclusion

The GO-CAM model 646ff70100000611 accurately represents the biological mechanism by which RNF152 ubiquitinates RagA to regulate mTORC1 signaling through GATOR1. The model includes the essential molecular activities, causal relationships, and cellular contexts supported by the literature.

While there are opportunities for expansion to include additional components of this regulatory pathway, the current representation provides a clear and accurate depiction of the core mechanism. The model adheres to GO-CAM best practices for representing molecular activities and complex annotations.