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Now I'll review the GO-CAM model specifically looking for how it handles the annotation of SMAD6 arginine methylation inhibiting SMAD1 signaling:

Review of GO-CAM Model: gomodel:646ff70100002308

Model Overview

The GO-CAM model (646ff70100002308) titled "SMAD6 arginine methylation inhibits SMAD1 signaling (Human)" represents a key molecular pathway in the regulation of BMP (Bone Morphogenetic Protein) signaling in humans. This model captures how SMAD6 arginine methylation, facilitated by PRMT1, regulates BMP-induced SMAD1 signaling.

Biological Context

BMP signaling is essential for various developmental processes including bone and cartilage formation, and is regulated through a complex signaling cascade involving SMAD proteins. The model specifically illustrates how SMAD6 (an inhibitory SMAD) is methylated by PRMT1 (Protein Arginine N-Methyltransferase 1), which enables SMAD6 to sequester SMAD1 and prevent its complex formation with SMAD4, thereby inhibiting downstream transcriptional activation.

Model Structure and Molecular Activities

The model includes five key activities:

  1. BMP4 cytokine activity (GO:0005125) enabled by UniProtKB:P12644 in extracellular space (GO:0005615)
  2. Part of BMP signaling pathway (GO:0030509)

  3. Provides input for PRMT1 protein-arginine N-methyltransferase activity

  4. PRMT1 protein-arginine N-methyltransferase activity (GO:0016274) enabled by UniProtKB:Q99873 in cytoplasm (GO:0005737)

  5. Part of regulation of BMP signaling pathway (GO:0030510)

  6. Directly positively regulates SMAD6 protein sequestering activity

  7. SMAD6 protein sequestering activity (GO:0140311) enabled by UniProtKB:O43541 in cytoplasm (GO:0005737)

  8. Part of negative regulation of BMP signaling pathway (GO:0030514)

  9. Inhibits protein-substrate adopter activity of SMAD1 (RO:0012010)

  10. SMAD1 DNA-binding transcription factor activity (GO:0003700) enabled by UniProtKB:Q15797 in nucleus (GO:0005634)

  11. Part of BMP signaling pathway (GO:0030509)

  12. SMAD4 DNA-binding transcription activator activity (GO:0001228) enabled by UniProtKB:Q13485 in nucleus (GO:0005634)

  13. Part of BMP signaling pathway (GO:0030509)
  14. Directly positively regulates SMAD1 DNA-binding transcription factor activity

Evidence Support

The model is well-supported by evidence from multiple publications, with the primary evidence coming from PMID:33667543, which specifically investigates how arginine methylation of R81 in SMAD6 confines BMP-induced SMAD1 signaling. All activities and causal relationships are backed by experimental evidence (ECO:0000314 - direct assay evidence used in manual assertion).

Evaluation

Strengths of the Model

  1. Accurate molecular representation: The model correctly captures the mechanism by which PRMT1 methylates SMAD6, enabling it to sequester SMAD1 and prevent SMAD1-SMAD4 complex formation.

  2. Evidence-based annotations: All associations are supported by appropriate evidence codes and references to primary literature.

  3. Complete pathway representation: The model includes the initiating signal (BMP4), the key regulatory mechanism (SMAD6 methylation by PRMT1), and the downstream effects (inhibition of SMAD1-SMAD4 complex formation).

  4. Proper subcellular localization: The model correctly indicates the subcellular localization of each activity (extracellular space for BMP4, cytoplasm for PRMT1 and SMAD6, nucleus for SMAD1 and SMAD4).

  5. Appropriate causal relationships: The causal relationships between activities are correctly represented using appropriate relation ontology terms (RO:0002407, RO:0002629, RO:0012010, RO:0002629).

Potential Improvements

  1. Specific methylation site: While the model title specifies arginine methylation, the specific methylation site (R81) described in the literature could be captured more explicitly in the model. Based on the referenced PMID, SMAD6 is methylated specifically at arginine 81 (R81), which is crucial for its ability to bind to phosphorylated SMAD1.

  2. BMP receptor interaction: The model could be expanded to include the interaction of BMP4 with its receptors (BMPR1A/BMPR2), which is the initial step in activating the signaling cascade.

  3. SMAD1 phosphorylation: The model doesn't explicitly capture the phosphorylation of SMAD1 by the BMP receptor, which is a critical step that makes SMAD1 a target for SMAD6-mediated sequestration.

  4. Nuclear translocation: While the model indicates the nuclear localization of SMAD1 and SMAD4, it doesn't explicitly represent the inhibition of SMAD1 nuclear translocation by SMAD6, which is an important aspect of the regulatory mechanism.

Compliance with GO-CAM Best Practices

The model adheres to GO-CAM best practices for representing complexes and molecular activities:

  1. Activity representation: Activities are appropriately represented with specific molecular functions enabled by specific gene products.

  2. Causal relationships: The causal relationships between activities are correctly specified using appropriate relation ontology terms.

  3. Cellular context: All activities are placed in their appropriate cellular contexts.

  4. Evidence support: All annotations are supported by appropriate evidence codes and references.

Conclusion

Overall, this GO-CAM model (gomodel:646ff70100002308) provides an accurate and well-supported representation of how SMAD6 arginine methylation by PRMT1 inhibits SMAD1 signaling in the BMP pathway. The model is consistent with current knowledge about this regulatory mechanism and follows GO-CAM best practices.

The model could be enhanced by explicitly representing the specific methylation site (R81), including BMP receptor interactions, capturing SMAD1 phosphorylation, and representing the inhibition of SMAD1 nuclear translocation. However, these suggestions do not detract from the overall quality and accuracy of the existing model.