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Now, let me review the GO-CAM model based on all the information gathered:

GO-CAM Model Review - gomodel:57c82fad00000695 (F13a1 and F13b-mouse-blood clotting)

Overview

The model gomodel:57c82fad00000695 describes the roles of Factor XIII subunits (A and B) in blood coagulation in mouse. It models the interactions between Factor XIII subunits and their regulation by thrombin (F2) in the context of blood clot formation.

Molecular Components in the Model

  1. F13a1 (MGI:MGI:1921395) - Coagulation factor XIII, A1 subunit, the catalytic subunit with protein-glutamine gamma-glutamyltransferase activity
  2. F13b (MGI:MGI:88379) - Coagulation factor XIII, B subunit, a non-catalytic subunit that binds to F13a1
  3. F2 (MGI:MGI:88380) - Coagulation factor II (Thrombin), with serine-type endopeptidase activity

Biological Process and Pathway Represented

The model describes blood coagulation (GO:0007596) and specifically the fibrin clot formation (GO:0072378) pathway, where thrombin (F2) activates Factor XIII by cleaving the A subunit (F13a1), while the B subunit (F13b) regulates this process. When activated, Factor XIII cross-links fibrin to stabilize blood clots.

Review of Model Structure and Causal Relationships

Structure Analysis

The model includes four activity nodes: 1. F13b with unspecified molecular function (GO:0003674) - part of generic biological process (GO:0008150) 2. F2 with serine-type endopeptidase activity (GO:0004252) 3. F13a1 with protein-glutamine gamma-glutamyltransferase activity (GO:0003810) 4. F13b with protein binding activity (GO:0005515) - part of blood coagulation (GO:0007596)

Causal Relationships

The model shows three causal relationships: 1. F2 directly positively regulates (RO:0002629) F13a1's protein-glutamine gamma-glutamyltransferase activity 2. F2 directly negatively regulates (RO:0002630) F13b's protein binding activity 3. F13b directly negatively regulates (RO:0002630) F13a1's protein-glutamine gamma-glutamyltransferase activity

Literature Support

The model is supported by PMID:18224415, which describes a study of F13b knockout mice. The paper shows that F13b helps maintain F13a1 levels in circulation and that both subunits are important for normal blood clotting. The evidence indicates that thrombin activates F13a1 by cleaving an amino-terminal activation peptide, resulting in dissociation from F13b in the presence of calcium, allowing F13a1 to cross-link fibrin.

The model is also supported by PMID:18398001 for F2's serine-type endopeptidase activity.

Issues and Recommendations

  1. Inconsistency in F13b representation: The model has two separate activities for F13b - one with molecular function [GO:0003674] and another with protein binding [GO:0005515]. This is confusing and redundant. According to GO-CAM best practices for representing complexes, a protein should have a single molecular function node.

  2. Missing complex representation: The literature clearly indicates F13a1 and F13b form a complex (A2B2 heterotetramer), but this is not explicitly modeled. The model should include a complex formation step.

  3. Incomplete pathway representation: The model should include the downstream effects of activated F13a1 on fibrin cross-linking to better represent the full biological pathway.

  4. Evidence quality: The F13b protein binding activity is supported by "physical interaction evidence" (ECO:0000353) but the context of this evidence could be better clarified in the model.

  5. Biological process consistency: F13b has two activities that are part of different biological processes (GO:0008150 and GO:0007596). This is inconsistent with the known role of F13b in blood coagulation.

  1. Represent F13b with a single activity node related to protein binding and part of blood coagulation.

  2. Add a complex formation step showing F13a1 and F13b forming the Factor XIII complex.

  3. Include the downstream steps of the pathway to show how activated F13a1 cross-links fibrin.

  4. Clarify the evidence supporting the protein binding activity of F13b.

  5. Ensure all activities are consistently annotated to the appropriate biological processes.

Conclusion

This GO-CAM model provides a reasonable representation of Factor XIII regulation in blood clotting, supported by relevant literature. However, it could be improved by addressing the issues noted above to better reflect the biological reality and conform to GO-CAM best practices.