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Based on my review of the model, the molecular roles, and the relevant literature, I'm ready to provide a comprehensive evaluation of GO-CAM model gomodel:61e0e55600000407.

GO-CAM Model Review: gomodel:61e0e55600000407 "SP_GADD34- PPP1CA"

Summary of the Model

This model (available at https://bioregistry.io/go.model:61e0e55600000407) represents the molecular pathway involving GADD34 (PPP1R15A), PPP1CA (PP1 catalytic subunit), and EIF2S1 (eIF2-alpha) in regulating translation initiation in response to cellular stress. The model describes how protein kinases EIF2AK2, EIF2AK3, and EIF2AK4 phosphorylate EIF2S1 to inhibit translation, and how the GADD34-PPP1CA complex acts to dephosphorylate EIF2S1 and restore translation.

Biological Accuracy

The model accurately captures the key components of the integrated stress response pathway:

  1. Protein kinases (EIF2AK2, EIF2AK3, EIF2AK4) correctly shown to negatively regulate EIF2S1's translation initiation activity through phosphorylation
  2. GADD34 (PPP1R15A) correctly shown with molecular adaptor activity that recruits PPP1CA to EIF2S1
  3. PPP1CA correctly shown with phosphatase activity that reverses EIF2S1 phosphorylation
  4. EIF2S1 correctly shown with translation initiation factor activity

The literature confirms this model accurately captures how GADD34-PPP1CA complex functions to dephosphorylate EIF2S1, consistent with the findings in PMID:26095357, which explains the molecular basis of this interaction and how GADD34 acts as a scaffold to bring together PPP1CA and EIF2S1.

GO-CAM Best Practices Compliance

The model largely follows GO-CAM best practices:

  1. Molecular Functions (MF): Appropriate molecular functions are assigned to each protein:
  2. EIF2AK2: protein serine/threonine kinase activity (GO:0004674)
  3. EIF2AK3 and EIF2AK4: protein kinase activity (GO:0004672)
  4. PPP1R15A and PPP1R15B: molecular adaptor activity (GO:0060090)
  5. PPP1CA: phosphatase activity (GO:0016791)

  6. EIF2S1: translation initiation factor activity (GO:0003743)

  7. Causal Relationships: The model uses appropriate causal relationships:

  8. "directly negatively regulates" (RO:0002630) for the kinases inhibiting EIF2S1

  9. "directly positively regulates" (RO:0002629) for PPP1R15A activating PPP1CA

  10. Cell Components (CC): Appropriate cellular locations are specified:

  11. EIF2AK3, PPP1R15A, and PPP1CA are indicated to occur in the endoplasmic reticulum (GO:0005783)

  12. EIF2S1 is indicated to occur in the cytoplasm (GO:0005737)

  13. Biological Processes (BP): Some proteins in the model include appropriate biological processes:

  14. EIF2AK3 is part of "response to endoplasmic reticulum stress" (GO:0034976)
  15. EIF2AK4 is part of "response to amino acid starvation" (GO:1990928)

Areas for Improvement

While the model is generally well-constructed, I've identified several areas for improvement:

  1. Missing Biological Process for EIF2S1: EIF2S1's activity should be placed in the context of a relevant biological process, such as "translational initiation" (GO:0006413) or "regulation of translational initiation in response to stress" (GO:0043558).

  2. Missing Cell Component for EIF2AK2 and EIF2AK4: These kinases lack cellular component annotations. EIF2AK2 is known to function in both cytoplasm and nucleus, while EIF2AK4 can be found in the cytoplasm.

  3. Inconsistent Annotation of Evidence: Some associations include evidence codes and citations (ECO:0000314 with PMIDs), while others lack evidence codes. Consistent use of evidence throughout the model would improve its quality.

  4. Missing Biological Process for PPP1CA: PPP1CA's role in dephosphorylation is not placed in any biological process context. It could be part of "protein dephosphorylation" (GO:0006470) or, more specifically, "regulation of translational initiation in response to stress" (GO:0043558).

  5. Regulatory Relationship Between PPP1R15A and EIF2S1: While the model shows PPP1R15A regulating PPP1CA which then regulates EIF2S1, the literature (PMID:26095357) indicates PPP1R15A directly interacts with EIF2S1 independent of PPP1CA. This interaction could be explicitly represented in the model, showing that PPP1R15A acts as a scaffold bringing together both PPP1CA and EIF2S1.

Conclusion

Model gomodel:61e0e55600000407 provides an accurate representation of the GADD34/PPP1CA/EIF2S1 pathway involved in translational regulation during stress. The model correctly captures the key molecular activities, causal relationships, and cellular localizations. Minor improvements could be made in the annotation of biological processes, cellular components, and evidence codes to fully adhere to GO-CAM best practices.

The model successfully illustrates how EIF2S1 phosphorylation by stress-activated kinases inhibits translation, and how the GADD34-PPP1CA complex reverses this inhibition by dephosphorylating EIF2S1. This pathway is critical in the cellular response to various stresses, including ER stress and amino acid starvation, and in the regulation of protein synthesis during stress recovery.