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Based on a thorough review of the model and associated information, I'll now provide a comprehensive review of the GO-CAM model "gomodel:5f46c3b700002102" titled "SPModule-TIRAP-MYDDOSOME".

Review of GO-CAM Model: SPModule-TIRAP-MYDDOSOME (gomodel:5f46c3b700002102)

1. Model Overview

This GO-CAM model represents the TIRAP-MYDDOSOME signaling complex, which is a key component in TLR/IL-1R signaling. The model shows a sequential recruitment and activation pathway involving four proteins:

  1. TIRAP/MAL (UniProtKB:P58753) - Toll/IL-1 receptor domain-containing adapter protein
  2. MYD88 (UniProtKB:Q99836) - Myeloid differentiation primary response protein
  3. IRAK4 (UniProtKB:Q9NWZ3) - Interleukin-1 receptor-associated kinase 4
  4. IRAK1 (UniProtKB:P51617) - Interleukin-1 receptor-associated kinase 1
  5. TRAF6 (UniProtKB:Q9Y4K3) - TNF receptor-associated factor 6

The model depicts a signaling cascade where each protein in the pathway directly positively regulates (RO:0002629) the next protein in the sequence, ultimately leading to TRAF6 ubiquitin-ubiquitin ligase activity.

2. Scientific Accuracy

The model accurately represents the known biology of the TIRAP-MYDDOSOME signaling pathway:

  • The model correctly shows TIRAP initiating the signaling cascade at the cell surface, which matches its known role as a TLR adaptor protein that recruits MYD88 to TLR2 and TLR4 complexes.
  • The sequential assembly of the Myddosome complex with MYD88 recruiting IRAK4, and IRAK4 recruiting IRAK1 is consistent with the literature (PMID:20485341).
  • The kinase activities of IRAK4 and IRAK1 are accurately represented.
  • The model appropriately ends with TRAF6 ubiquitin-ubiquitin ligase activity, which is consistent with TRAF6's role in this pathway.

3. Completeness and Molecular Function Annotations

Each protein in the model is annotated with its appropriate molecular function:

  • TIRAP: Annotated with "molecular adaptor activity" (GO:0060090), which is appropriate for its role in recruiting MYD88.
  • MYD88: Annotated with "molecular adaptor activity" (GO:0060090), consistent with its role in TLR signaling.
  • IRAK4: Annotated with "kinase activity" (GO:0016301), which correctly represents its enzymatic function.
  • IRAK1: Annotated with "kinase activity" (GO:0016301), which correctly represents its enzymatic function.
  • TRAF6: Annotated with "ubiquitin-ubiquitin ligase activity" (GO:0034450), which is appropriate for its E3 ligase function.

4. Cellular Component Annotations

All proteins are annotated with appropriate cellular locations:

  • TIRAP: Located at "cell surface" (GO:0009986), which is appropriate as it recruits MyD88 to cell surface TLR complexes.
  • MYD88: Located at "cell surface" (GO:0009986), consistent with its recruitment by TIRAP.
  • IRAK4: Located at "cell surface" (GO:0009986), which is appropriate for its recruitment to the receptor complex.
  • IRAK1: Located at "cell surface" (GO:0009986), correctly reflecting its location in the Myddosome complex.
  • TRAF6: Located at "cytoplasm" (GO:0005737), which is appropriate as TRAF6 dissociates from the receptor complex following activation.

5. Causal Relations

The causal relationships in the model use the appropriate relation (RO:0002629 "directly positively regulates"), which correctly captures the direct positive regulatory relationships between the proteins in this signaling cascade:

  • TIRAP directly positively regulates MYD88
  • MYD88 directly positively regulates IRAK4
  • IRAK4 directly positively regulates IRAK1
  • IRAK1 directly positively regulates TRAF6

6. Evidence

Each activity and causal relation is supported by appropriate experimental evidence:

  • Evidence codes used are primarily ECO:0000314 (direct assay evidence used in manual assertion)
  • Literature references are provided for each assertion (e.g., PMID:14625308, PMID:22851693, PMID:9734363, PMID:11960013, PMID:20485341, PMID:15465037)
  • All assertions have appropriate provenance information with contributor ORCID and dates

7. Compliance with GO-CAM Best Practices

The model follows GO-CAM best practices for representing protein complexes as outlined in the document "How_to_annotate_complexes_in_GO-CAM":

  • The model correctly uses individual proteins when the subunits that carry specific molecular activities are known, rather than using a complex ID.
  • The model appropriately represents the sequential assembly and activation of the complex through causal relations between the individual proteins.

8. Areas for Improvement

While the model is scientifically accurate and well-constructed, I have a few minor suggestions for improvement:

  1. Additional Context: The model could potentially benefit from additional context by connecting to upstream TLR activation or downstream events beyond TRAF6.

  2. Complex Formation: While the model implies complex formation through the causal relations, it might be valuable to explicitly annotate the formation of the Myddosome complex.

  3. Additional TRAF6 Relations: TRAF6 activates multiple downstream pathways (NF-κB, MAP kinases). Including some of these downstream targets could enhance the model's biological completeness.

9. Conclusion

The GO-CAM model "gomodel:5f46c3b700002102" (SPModule-TIRAP-MYDDOSOME) is a scientifically accurate, well-constructed representation of the TIRAP-MYDDOSOME signaling pathway. It correctly captures the sequential assembly and activation of this important signaling complex in TLR/IL-1R pathways, with appropriate molecular functions, cellular components, causal relations, and supporting evidence.

The model effectively represents how TIRAP recruits MYD88 to TLR signaling complexes, which then recruits IRAK4, leading to the recruitment and activation of IRAK1, and ultimately activating TRAF6. This accurately reflects our current understanding of this signaling pathway as supported by the primary literature.