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After reviewing all the information, I'll now provide a detailed assessment of the GO-CAM model gomodel:63894f2500000740.

Review of GO-CAM Model: gomodel:63894f2500000740

Model Overview

  • Title: FIP200 ubiquitination by TRIM21 leading to autophagy inhibition (Human)
  • Taxon: Human (NCBITaxon:9606)
  • Status: Production

Model Content Analysis

This model depicts a molecular pathway where TRIM21 (P19474) ubiquitinates FIP200/RB1CC1 (Q8TDY2), which leads to the inhibition of autophagy. The model also includes involvement of SETD2 (Q9BYW2) methyltransferase.

Key Activities and Associations

  1. SETD2 Activity (Q9BYW2):
  2. Molecular function: Protein-lysine N-methyltransferase activity (GO:0016279)
  3. Part of: Positive regulation of autophagy (GO:0010508)
  4. Negatively regulates: TRIM21's ubiquitin protein ligase activity

  5. Evidence: ECO:0000314 (direct assay evidence) from PMID:28753426

  6. TRIM21 Activity (P19474):

  7. Molecular function: Ubiquitin protein ligase activity (GO:0061630)
  8. Occurs in: Cytoplasm (GO:0005737)
  9. Part of: Protein K48-linked ubiquitination (GO:0070936)
  10. Negatively regulates: FIP200/RB1CC1's protein kinase binding

  11. Evidence: ECO:0000314 (direct assay evidence) from PMID:36359729

  12. FIP200/RB1CC1 Activity (Q8TDY2):

  13. Molecular function: Protein kinase binding (GO:0019901)
  14. Occurs in: ATG1/ULK1 kinase complex (GO:1990316)
  15. Part of: Autophagosome assembly (GO:0000045)
  16. Target of TRIM21's negative regulation

Quality Control Assessment

Strengths

  1. Scientific Accuracy:
  2. The model accurately represents the molecular mechanism described in PMID:36359729, which shows that TRIM21 ubiquitinates FIP200 at K1133, leading to its degradation and inhibiting autophagy.

  3. The representation of SETD2's role in methylating FIP200, which prevents TRIM21-mediated ubiquitination, is consistent with the literature.

  4. Logical Structure:

  5. The causal connections using RO:0002630 (directly negatively regulates) are appropriate.

  6. The directional flow from SETD2 inhibiting TRIM21 activity, and TRIM21 inhibiting FIP200 activity is logical.

  7. Proper Evidence:

  8. Evidence codes are correctly used (ECO:0000314 for direct assay evidence).
  9. All assertions are backed by appropriate literature references.

Areas for Improvement

  1. Complex Representation:

  2. According to the "How to annotate complexes in GO-CAM" guidance, FIP200/RB1CC1 is part of the ATG1/ULK1 kinase complex. The model correctly notes this, but could be enhanced by including more detailed information about other complex members that might be affected.

  3. Molecular Detail:

  4. The specific lysine residue (K1133) on FIP200 that gets methylated by SETD2 and ubiquitinated by TRIM21 is not explicitly mentioned in the model, though it's a key detail in the paper.

  5. The model doesn't explicitly capture that ubiquitination leads to protein degradation via the proteasome pathway, which is the mechanism of inhibition.

  6. Duplicate Causal Association:

  7. There appears to be a duplicate causal association from SETD2 to TRIM21 (two instances of RO:0002630), with one of them lacking evidence, which should be removed or properly annotated.

  8. Biological Process Context:

  9. While the model does include that FIP200 is part of autophagosome assembly (GO:0000045), it could more clearly represent that TRIM21-mediated degradation of FIP200 specifically affects autophagy initiation, as described in the paper.

Consistency with GO-CAM Best Practices

  1. Appropriate Use of Predicates:

  2. The model correctly uses RO:0002630 (directly negatively regulates) to indicate inhibition.

  3. Cellular Compartment Annotation:

  4. The model correctly places TRIM21 in the cytoplasm and FIP200 in the ATG1/ULK1 kinase complex.

  5. Evidence and References:

  6. All activities have appropriate evidence codes and references, which is in line with best practices.

Recommendations for Improvement

  1. Remove Duplicate Causal Association:

  2. There's a duplicate causal association from SETD2 to TRIM21 with no evidence, which should be removed.

  3. Add Detail about Mechanism:

  4. Consider adding annotations to explicitly indicate that TRIM21-mediated ubiquitination leads to proteasomal degradation of FIP200.

  5. Specify Modification Site:

  6. Consider adding a note about K1133 being the specific site of both methylation and ubiquitination, which is key to the competitive mechanism.

  7. Complete the Pathway Context:

  8. The model could better represent that this mechanism regulates autophagy initiation rather than just general autophagy.

Conclusion

Overall, this GO-CAM model (gomodel:63894f2500000740) provides a good representation of the molecular interactions involved in TRIM21-mediated ubiquitination of FIP200 and its inhibition by SETD2-mediated methylation. The model accurately captures the key molecular functions and biological processes described in the literature.

The model could be improved by removing the duplicate causal association, adding more details about the specific modification site and mechanism of inhibition, and more clearly representing the impact on autophagy initiation. These refinements would make the model more informative and precise for users seeking to understand this regulatory pathway.