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Based on my review of this GO-CAM model and all the information I've gathered, I'll now provide my comprehensive review of gomodel:66187e4700000246.

Review of GO-CAM Model: gomodel:66187e4700000246

Summary of the Model

This model (gomodel:66187e4700000246) describes "The CRL5(ASB9) complex mediates ubiquitination and degradation of CKB (Human)." It represents a specific biochemical pathway where the CRL5(ASB9) E3 ubiquitin-ligase complex targets creatine kinase B-type (CKB) for ubiquitination and subsequent proteasomal degradation in humans.

The model shows several key activities connected through causal relationships: 1. CKB (UniProtKB:P12277) performing creatine kinase activity (GO:0004111) as part of phosphocreatine biosynthetic process (GO:0046314) 2. CUL5 (UniProtKB:Q93034) performing ubiquitin ligase complex scaffold activity (GO:0160072) as part of proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161) 3. ASB9 (UniProtKB:Q96DX5) performing ubiquitin-like ligase-substrate adaptor activity (GO:1990756) as part of proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161) 4. RNF7 (UniProtKB:Q9UBF6) performing ubiquitin protein ligase activity (GO:0061630) as part of proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161) 5. RNF7 also performing NEDD8 ligase activity (GO:0061663) as part of protein neddylation (GO:0045116) 6. ARIH2 (UniProtKB:O95376) performing ubiquitin protein ligase activity (GO:0061630) as part of proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161)

The causal connections show: - CUL5 directly positively regulates (RO:0002629) ASB9's adaptor activity - ASB9 provides input for (RO:0002413) RNF7's ubiquitin ligase activity - RNF7 directly positively regulates (RO:0002629) ARIH2's ubiquitin ligase activity - ARIH2 directly negatively regulates (RO:0002630) CKB's creatine kinase activity

Evidence and Literature Support

The model is well-supported by evidence from multiple publications: - The creatine kinase activity of CKB is supported by PMID:8186255, which established the catalytic site of creatine kinase through site-directed mutagenesis. - The ubiquitination mechanisms and complex interactions are supported by PMID:33268465, which provides detailed mechanistic insight into how NEDD8 activation of CUL5 ubiquitin E3 ligases works, particularly focusing on the ASB9-CRL E3 ligase complex and its targeting of CKB. - The NEDD8 ligase activity is supported by PMID:19250909.

Biological Accuracy and Consistency

The model accurately represents the molecular mechanism discovered in the literature. It correctly shows:

  1. The CRL5(ASB9) complex consisting of:
  2. CUL5 as the scaffold
  3. ASB9 as the substrate recognition component

  4. RNF7 (also known as RBX2 or SAG) as the RING component

  5. The regulatory mechanism where:

  6. RNF7 performs protein neddylation, which is a prerequisite for the complex's activity
  7. ASB9 recognizes and binds to the substrate (CKB)
  8. ARIH2 works with the CRL5 complex to catalyze the ubiquitination of CKB

  9. Ubiquitination of CKB leads to its degradation, effectively negatively regulating its activity

  10. The model correctly depicts that ARIH2 is essential for the complex to effectively ubiquitinate CKB, as shown in the literature. PMID:33268465 specifically demonstrates that ARIH2 is required for efficient ubiquitination of CKB by the ASB9-CRL complex.

Alignment with GO-CAM Best Practices

The model follows GO-CAM best practices for representing complexes, as outlined in the "How to annotate complexes in GO-CAM" document:

  1. The activities are attributed to the specific proteins that carry them (option 1 in the guidelines), rather than to the complex as a whole, which is appropriate since the roles of the individual components are well-characterized.

  2. The scaffold activity of CUL5 is represented first, properly activating subsequent activities from other components of the complex.

  3. The causal connections follow the standard predicates correctly:

  4. "directly positively regulates" (RO:0002629) is used properly to show activation relationships
  5. "provides input for" (RO:0002413) is used properly to show sequential process connections
  6. "directly negatively regulates" (RO:0002630) is used properly to show the inhibitory effect of ubiquitination on CKB

Areas for Potential Improvement

  1. Additional Molecular Details: The model could potentially be expanded to include the specific E2 ubiquitin-conjugating enzymes that work with this E3 ligase complex. The literature mentions UBE2L3 and other E2s that can contribute to polyubiquitination.

  2. Ubiquitination Sites: The model could potentially annotate the specific lysine residues on CKB that are targeted for ubiquitination (K45, K101, K107, and K381) as identified in PMID:33268465.

  3. ELOB/ELOC Components: The literature describes elongin B and elongin C (ELOB/C) as components of the CRL5 complex, but these are not represented in the current model. Adding these components could provide a more complete picture of the complex.

  4. Neddylation Details: While the model includes the neddylation activity, it could potentially specify that CUL5 is neddylated at K724, which is important for the recruitment of ARIH2 (as described in PMID:33268465).

Conclusion

Overall, this is a well-constructed GO-CAM model that accurately represents the current understanding of how the CRL5(ASB9) E3 ubiquitin ligase complex targets CKB for degradation. The model effectively captures the key proteins, activities, and causal relationships involved in this process, with strong literature support for all assertions. It follows GO-CAM best practices for representing complexes and their activities.

The model provides a valuable contribution to the GO-CAM knowledge base by representing a specific example of selective protein degradation through the ubiquitin-proteasome system, which is a fundamental cellular process with implications for numerous biological functions and disease mechanisms.