Skip to content

Based on the information gathered, I'll now provide a comprehensive review of GO-CAM model gomodel:61e0e55600000624 "Cyclin-D ubiquitination and degradation by AMBRA1 (Human)":

GO-CAM Model Review: Cyclin-D ubiquitination and degradation by AMBRA1 (Human)

Model ID: gomodel:61e0e55600000624

Summary

This model represents the molecular mechanism by which AMBRA1 regulates cell cycle progression through the ubiquitination and degradation of D-type cyclins (Cyclin D1, D2, and D3) during the G1/S transition of the cell cycle in humans. AMBRA1 functions as a substrate adaptor in a DCX (DDB1-CUL4-X-box) E3 ubiquitin ligase complex that targets phosphorylated cyclin D proteins for degradation.

Key Components

  1. AMBRA1 (Q9C0C7): Substrate-recognition component (adaptor) in the DCX E3 ubiquitin-protein ligase complex
  2. Cyclin D proteins:
  3. Cyclin D1 (P24385)
  4. Cyclin D2 (P30279)
  5. Cyclin D3 (P30281)
  6. CDK proteins:
  7. CDK4 (P11802)
  8. CDK6 (Q00534)

Strengths of the Model

  1. Proper annotation of ubiquitin ligase adaptor activity: AMBRA1 is correctly annotated with the molecular function "ubiquitin-like ligase-substrate adaptor activity" (GO:1990756) and is properly associated with "proteasome-mediated ubiquitin-dependent protein catabolic process" (GO:0043161).

  2. Accurate cell cycle context: The model appropriately places all activities within the "G1/S transition of mitotic cell cycle" (GO:0000082) biological process.

  3. Multiple cyclins represented: The model includes all three D-type cyclins (D1, D2, and D3) with appropriate molecular functions.

  4. Appropriate causal relationships: The model uses the RO:0002409 predicate ("causally upstream of") to link AMBRA1's substrate adaptor activity to the cyclin-CDK complexes, which is appropriate given its regulatory role in targeting cyclins for degradation.

  5. Evidence support: The model cites appropriate literature evidence, including the key papers (PMID:33854235, PMID:33854239) that establish AMBRA1's role in cyclin D regulation.

Issues Identified

  1. Inconsistent causal relationships: There is a mix of causal predicates used in the model. For example:
  2. In some cases, RO:0002409 "causally upstream of" is used
  3. In other cases, RO:0002630 "directly negatively regulates" is used

  4. According to E3 ubiquitin ligase annotation guidelines, for an adaptor protein like AMBRA1, the relationship to the substrate should be "indirectly regulates" when the E3 ligase is not explicitly included in the model

  5. Missing components of the E3 ligase complex: The model does not include the other components of the DCX E3 ligase complex (CUL4 and DDB1), which would ideally be included according to the E3 ubiquitin ligase annotation guidelines.

  6. Redundant annotations: There are several redundant activities represented in the model:

  7. AMBRA1 has multiple instances with the same molecular function (GO:1990756)

  8. Some causal relationships are duplicated (e.g., there are two identical causal associations from activity ID "gomodel:61e0e55600000624/62183af000000905" to "gomodel:61e0e55600000624/61e0e55600000712")

  9. Evidence assignment: Some causal relationships lack explicit evidence annotations, making it difficult to trace the source of these assertions.

  10. Incomplete representation of the phosphorylation-dependent mechanism: While the model shows AMBRA1 targeting cyclins for degradation, it does not explicitly show the phosphorylation step of cyclin D (at Thr-286) that's required for recognition by AMBRA1, as described in the UniProt entries.

Recommendations for Improvement

  1. Standardize causal relationships: Use consistent causal relationship predicates according to the E3 ubiquitin ligase annotation guidelines.

  2. Add missing E3 ligase complex components: Include CUL4 and DDB1 with appropriate molecular functions (ubiquitin ligase complex scaffold activity - GO:0160072) to provide a more complete representation of the DCX complex.

  3. Remove redundant activities: Consolidate the multiple representations of AMBRA1's molecular function to reduce duplication.

  4. Complete the phosphorylation mechanism: Add the kinase activity that phosphorylates cyclin D at Thr-286, which is a prerequisite for recognition by AMBRA1.

  5. Add evidence to all assertions: Ensure each causal relationship has appropriate evidence annotations.

  6. Enhance mechanistic detail: Consider adding the specific ubiquitination at Lys-269 of cyclin D1 as mentioned in the UniProt entry.

Conclusion

The GO-CAM model "Cyclin-D ubiquitination and degradation by AMBRA1 (Human)" provides a valuable representation of AMBRA1's role in regulating cell cycle progression through targeted degradation of D-type cyclins. While the core biological mechanism is captured correctly, there are opportunities to enhance the model's completeness and consistency with GO-CAM best practices, particularly regarding E3 ubiquitin ligase complex representation and causal relationship annotations.

The model aligns with recent literature showing AMBRA1 as a key regulator of D-type cyclins that affects the G1/S transition, helping to ensure genomic integrity during DNA replication and counteracting developmental abnormalities and tumor growth.