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Now I'll review the model based on all the information gathered.

Review of GO-CAM Model: gomodel:641ce4dc00000430

Model Overview

This model titled "NOD2 localization to the plasma membrane following palmitoylation by ZDHHC5 (Human)" describes the palmitoylation of NOD2 protein by ZDHHC5, which enables NOD2's localization to the plasma membrane, leading to activation of signaling pathways through RIPK2 and XIAP proteins.

Biological Context

The model represents a crucial aspect of innate immune signaling. NOD2 is a cytosolic pattern recognition receptor that detects bacterial muramyl dipeptide (MDP). For NOD2 to function properly, it must be localized to the plasma membrane, which is facilitated by palmitoylation (the addition of palmitate to specific cysteine residues). This post-translational modification increases NOD2's affinity for membrane bilayers and is essential for its ability to activate downstream signaling.

Model Structure

The model consists of four main activities:

  1. ZDHHC5 (UniProtKB:Q9C0B5) with protein-cysteine S-palmitoyltransferase activity (GO:0019706)
  2. NOD2 (UniProtKB:Q9HC29) with pattern recognition receptor activity (GO:0038187)
  3. RIPK2 (UniProtKB:O43353) with signaling adaptor activity (GO:0035591)
  4. XIAP (UniProtKB:P98170) with ubiquitin protein ligase activity (GO:0061630)

Causal Flow

The causal flow in the model is: - ZDHHC5 palmitoylates NOD2 (RO:0002629 - directly positively regulates) - NOD2 then activates RIPK2 (RO:0002629 - directly positively regulates) - RIPK2 activates XIAP (RO:0002629 - directly positively regulates)

Cellular Context

  • ZDHHC5 occurs in the plasma membrane (GO:0005886)
  • NOD2 occurs in the plasma membrane (GO:0005886) after palmitoylation
  • RIPK2 occurs in the plasma membrane (GO:0005886)
  • XIAP occurs in the cytoplasm (GO:0005737)

Biological Processes

  • ZDHHC5 is part of protein localization to plasma membrane (GO:0072659)
  • NOD2 is part of response to muramyl dipeptide (GO:0032495)
  • RIPK2 is part of NOD2 signaling pathway (GO:0070431)
  • XIAP is part of protein K63-linked ubiquitination (GO:0070534)

Evidence Assessment

The model is well-supported by evidence from multiple peer-reviewed publications:

  • The role of ZDHHC5 in palmitoylating NOD2 is supported by PMID:34293401 and PMID:31649195
  • The localization of NOD2 to the plasma membrane is supported by PMID:17355968
  • The interaction between NOD2 and RIPK2 is supported by PMID:17355968
  • The regulation of RIPK2 by XIAP through ubiquitination is supported by PMID:29452636

Each annotation is backed by direct experimental evidence (ECO:0000314), which is appropriate.

Quality Control Assessment

Strengths

  1. The model accurately captures the sequential steps in NOD2 activation, from palmitoylation to downstream signaling.
  2. The cellular locations are accurately represented.
  3. The causal relationships are appropriately modeled using the correct predicates.
  4. The evidence is well-documented with appropriate PMIDs and evidence codes.
  5. The model includes key proteins and their verified molecular functions.

Potential Issues or Improvements

  1. Palmitoylation Sites: While the model represents the palmitoylation activity, it could be enhanced by noting the specific cysteine residues in NOD2 (C395 and C1033) that are palmitoylated, as indicated in PMID:34293401.

  2. Intermediate Steps: The model represents a direct relationship between RIPK2 and XIAP, which is accurate, but there could be more detail on the mechanism. XIAP mediates K63-linked polyubiquitination of RIPK2, transforming it into a scaffolding protein for downstream effectors.

  3. Downstream Effects: The model could be extended to include the downstream effects of XIAP-mediated ubiquitination of RIPK2, such as activation of the NF-κB and MAP kinases signaling pathways.

  4. Biological Process Annotation: While NOD2 is correctly annotated as part of "response to muramyl dipeptide" (GO:0032495), it could also be annotated to "innate immune response" (GO:0045087) to provide more context.

Consistency with GO-CAM Guidelines

Based on the GO-CAM guidelines for annotating complexes and regulatory processes:

  1. The model correctly represents the individual proteins and their activities rather than using a complex ID, which is appropriate since the specific activities of each protein are known.

  2. The regulatory relationships are properly represented using the "directly positively regulates" (RO:0002629) predicate, which is correct for direct regulation.

  3. The cellular locations are accurately represented, consistent with how these proteins function in vivo.

Summary

This is a high-quality GO-CAM model that accurately represents the current understanding of NOD2 palmitoylation by ZDHHC5 and subsequent activation of signaling through RIPK2 and XIAP. The model captures a crucial post-translational modification (palmitoylation) that is essential for NOD2 function in innate immunity.

The model is consistent with GO-CAM best practices and is supported by strong experimental evidence from the literature. While there are minor opportunities for enhancement by adding more detail on specific residues and downstream effects, the core process is well-represented.