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Based on all the gathered information, I'll now conduct a comprehensive review of the GO-CAM model gomodel:636d9ce800001192.

Review of GO-CAM Model: gomodel:636d9ce800001192

Model Overview

  • Title: DCAF12 controls MOV10 during T cell activation. (Human)
  • Model ID: gomodel:636d9ce800001192
  • Taxon: Human (NCBITaxon:9606)
  • Status: Production

Model Summary

This GO-CAM model represents the molecular pathway by which the CRL4-DCAF12 ubiquitin ligase complex controls the levels of MOV10 RNA helicase during T cell activation in humans. The model describes how DCAF12 (Q5T6F0) acts as a substrate receptor in a CUL4A-based E3 ubiquitin ligase complex, recognizing the C-terminal acidic degron (glutamic acid-leucine motif) of MOV10 RNA helicase (Q9HCE1) and targeting it for ubiquitin-dependent degradation via the proteasome.

Model Components

The model consists of four main molecular activities:

  1. MOV10 RNA helicase activity (GO:0032574)
  2. Enabled by: MOV10 (UniProtKB:Q9HCE1)

  3. Part of: miRNA-mediated gene silencing by mRNA destabilization (GO:0035279)

  4. RBX1 ubiquitin protein ligase activity (GO:0061630)

  5. Enabled by: RBX1 (UniProtKB:P62877)
  6. Part of: ubiquitin-dependent protein catabolic process via the C-end degron rule pathway (GO:0140627)
  7. Location: Cytoplasm (GO:0005737)

  8. Causal connection: Directly negatively regulates (RO:0002630) MOV10 RNA helicase activity

  9. CUL4A ubiquitin ligase complex scaffold activity (GO:0160072)

  10. Enabled by: CUL4A (UniProtKB:Q13619)
  11. Part of: ubiquitin-dependent protein catabolic process via the C-end degron rule pathway (GO:0140627)
  12. Location: Cytoplasm (GO:0005737)

  13. Causal connection: Directly positively regulates (RO:0002629) DCAF12 ubiquitin-like ligase-substrate adaptor activity

  14. DCAF12 ubiquitin-like ligase-substrate adaptor activity (GO:1990756)

  15. Enabled by: DCAF12 (UniProtKB:Q5T6F0)
  16. Part of: ubiquitin-dependent protein catabolic process via the C-end degron rule pathway (GO:0140627)
  17. Location: Cell component (GO:0005575)
  18. Causal connection: Provides input for (RO:0002413) RBX1 ubiquitin protein ligase activity

Pathway Flow

The model's causal flow correctly represents the process by which the CRL4-DCAF12 complex regulates MOV10:

  1. CUL4A acts as a scaffold that positively regulates DCAF12 substrate adaptor activity
  2. DCAF12 acts as the substrate receptor that recognizes MOV10's C-terminal degron
  3. DCAF12 provides input for RBX1 ubiquitin ligase activity
  4. RBX1's ubiquitin ligase activity directly negatively regulates MOV10 RNA helicase activity

Literature Support and Evidence

The model is well-supported by the primary literature, particularly the paper PMID:34065512, which directly identifies MOV10 as a substrate of the CRL4-DCAF12 complex and demonstrates its role in T cell activation. The paper provides strong experimental evidence for each aspect of the model:

  1. DCAF12 directly recognizes the C-terminal -EL motif of MOV10
  2. This interaction leads to ubiquitination and proteasomal degradation of MOV10
  3. The process is particularly important during T cell activation
  4. The degradation of MOV10 is dependent on the CRL4 complex

Model Evaluation

Strengths:

  1. Accurate representation of the pathway: The model correctly represents the molecular functions and causal relationships described in the literature.
  2. Well-supported by evidence: Each activity and relationship is backed by experimental evidence from published literature.
  3. Appropriate GO terms: The molecular functions, cellular locations, and biological processes are represented with accurate GO terms.
  4. Proper relationship predicates: The causal connections use appropriate relationship predicates that accurately reflect the biology.

Concerns:

  1. Cellular location annotation for MOV10: MOV10's activity is annotated as occurring in "cellular_component" (GO:0005575), which is a root term. According to the literature, MOV10 is primarily located in the cytoplasm (specifically in P-bodies) during T cell activation. A more specific location term would improve the model.

  2. Evidence for MOV10 function: The MOV10 activity is supported by ECO:0000250 (sequence similarity evidence) with UniProtKB:P23249 as reference. While this is acceptable, direct experimental evidence would be stronger.

  3. Biological context: While the model correctly represents T cell activation in the title and context, it could benefit from explicitly connecting to T cell activation processes in the causal chain.

Recommendations for Improvement

  1. Update MOV10 location: Replace the general GO:0005575 term with a more specific term such as GO:0000932 (P-body) or at minimum GO:0005737 (cytoplasm) to better reflect MOV10's subcellular location during T cell activation.

  2. Add additional supporting evidence: If available, include direct experimental evidence for MOV10's RNA helicase activity from human studies.

  3. Consider expanding the model: The paper mentions that this pathway is particularly important during T cell activation. Consider connecting this pathway to T cell activation processes (GO:0042110) more explicitly in the model.

  4. Possible expansion: Consider including the destabilization of the C-terminal degron motif (-EL) of MOV10 as part of the causal chain, as this is the specific recognition mechanism described in the paper.

Conclusion

The GO-CAM model gomodel:636d9ce800001192 provides an accurate and well-supported representation of the molecular pathway by which the CRL4-DCAF12 complex regulates MOV10 during T cell activation. The model follows the GO-CAM best practices for representing protein complexes by individually modeling the activities of each complex component with their specific molecular functions. With minor improvements to the location annotation for MOV10, this model will serve as an excellent resource for understanding this important regulatory mechanism in T cell biology.