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Now that I have gathered all the necessary information, I'll review GO-CAM model 617b481400000389.

Review of GO-CAM Model 617b481400000389

Model Overview

Title: KAT5 regulation of the cytoskeleton by acetylation of proteins (Human)
ID: gomodel:617b481400000389
Taxon: Human (NCBITaxon:9606)
Status: Production

This model describes how KAT5 (TIP60) regulates cytoskeletal processes during mitosis through acetylation of various proteins, focusing on how this affects chromosome segregation and kinetochore-microtubule attachment.

Overall Structure Analysis

The model consists of 6 activities connected through causal associations:

  1. AURKB kinase activities (two instances)
  2. KAT5 acetyltransferase activity
  3. SIRT1 deacetylase activity
  4. NDC80 kinetochore adaptor activity
  5. CDK1 kinase activity

The model demonstrates a regulatory cascade involving CDK1, KAT5, SIRT1, AURKB, and NDC80, all contributing to the regulation of mitotic sister chromatid segregation.

Molecular Activities and Annotations

1. AURKB (Aurora Kinase B) Activities:

Two AURKB-enabled activities are represented: - Activity 1 (617b481400000409): Protein serine/threonine kinase activity (GO:0004674) - Part of positive regulation of mitotic sister chromatid segregation (GO:0062033) - Evidence from PMID:26829474 - Enabled by UniProtKB:Q96GD4 (AURKB)

  • Activity 2 (617b481400000428): Protein serine/threonine kinase activity (GO:0004674)
  • Part of positive regulation of mitotic sister chromatid segregation (GO:0062033)
  • Evidence from PMID:30409912
  • Enabled by UniProtKB:Q96GD4 (AURKB)
  • Directly negatively regulates (RO:0002630) NDC80 activity

2. KAT5 (TIP60) Activity:

  • Activity (617b481400000400): Peptide-lysine-N-acetyltransferase activity (GO:0061733)
  • Occurs in kinetochore (GO:0000776)
  • Part of positive regulation of mitotic sister chromatid segregation (GO:0062033)
  • Evidence from PMID:26829474
  • Enabled by UniProtKB:Q92993 (KAT5/TIP60)
  • Directly positively regulates (RO:0002629) AURKB activity (617b481400000409)

3. SIRT1 Activity:

  • Activity (617b481400000440): NAD-dependent protein deacetylase activity (GO:0034979)
  • Part of negative regulation of attachment of mitotic spindle microtubules to kinetochore (GO:1902424)
  • Evidence from PMID:30409912
  • Enabled by UniProtKB:Q96EB6-2 (SIRT1 isoform 2)
  • Directly negatively regulates (RO:0002630) NDC80 activity

4. NDC80 Activity:

  • Activity (617b481400000435): Kinetochore adaptor activity (GO:0140483)
  • Part of attachment of mitotic spindle microtubules to kinetochore (GO:0051315)
  • Evidence from PMID:30409912
  • Enabled by UniProtKB:O14777 (NDC80/HEC1)

5. CDK1 Activity:

  • Activity (617b481400000447): Protein serine/threonine kinase activity (GO:0004674)
  • Part of positive regulation of mitotic sister chromatid segregation (GO:0062033)
  • Evidence from PMID:26829474
  • Enabled by UniProtKB:P06493 (CDK1)
  • Directly positively regulates (RO:0002629) KAT5 activity

Causal Relationships in the Model

The model presents the following causal relationships:

  1. CDK1 → KAT5 (positive regulation): CDK1 phosphorylates KAT5 at Ser-90, activating its acetyltransferase activity
  2. KAT5 → AURKB (positive regulation): KAT5 acetylates AURKB at Lys-215, enhancing its kinase activity
  3. AURKB → NDC80 (negative regulation): AURKB phosphorylates NDC80, affecting its kinetochore-microtubule attachment
  4. SIRT1 → NDC80 (negative regulation): SIRT1 deacetylates NDC80, counteracting the effect of KAT5-mediated acetylation

Evidence Assessment

The model is supported by two key publications:

  1. PMID:26829474 (Mo et al., 2016): This paper demonstrates that KAT5/TIP60 acetylates Aurora B at Lys-215, which protects Aurora B from dephosphorylation at Thr-232, ensuring accurate chromosome segregation. The paper also shows that CDK1 phosphorylates TIP60 at Ser-90, which enhances its acetyltransferase activity.

  2. PMID:30409912 (Zhao et al., 2019): This paper shows that KAT5/TIP60 acetylates NDC80/HEC1 at Lys-53 and Lys-59 during mitosis, promoting robust kinetochore-microtubule attachment. SIRT1 counteracts this by deacetylating NDC80/HEC1.

The evidence is strong, coming from primary research articles with experimental evidence (ECO:0000314), and all annotations have been sourced from peer-reviewed publications.

Accuracy and Completeness Assessment

The model accurately captures the regulatory roles of KAT5/TIP60 in mitotic processes through acetylation of key proteins (AURKB and NDC80). It correctly represents:

  1. The role of CDK1 in activating KAT5 through phosphorylation
  2. The role of KAT5 in activating AURKB through acetylation
  3. The opposing actions of KAT5 and SIRT1 on NDC80
  4. The impact of these activities on mitotic sister chromatid segregation and kinetochore-microtubule attachment

Consistency with GO-CAM Best Practices

The model follows GO-CAM best practices: - Each activity has properly annotated molecular function, cellular location (where applicable), and biological process - Causal relationships between activities are correctly specified using appropriate RO relations - Evidence codes and citations are provided for each annotation - The connections between activities form a coherent regulatory pathway

Suggestions for Improvement

While the model is well-constructed, a few additions could enhance it:

  1. Additional causal relationships: The model could include the direct acetylation of NDC80 by KAT5, which is described in PMID:30409912 but not explicitly modeled as a causal relationship.

  2. Molecular details: Adding annotations for the specific acetylation sites on AURKB (Lys-215) and NDC80 (Lys-53 and Lys-59) could provide more molecular detail.

  3. Additional components: The model could include other components of the CPC (Chromosomal Passenger Complex), such as INCENP, which is mentioned in the referenced papers as being important for AURKB function.

  4. Phosphorylation details: Adding annotations for the specific phosphorylation sites on KAT5 (Ser-90) and AURKB (Thr-232) would provide more molecular detail.

Conclusion

GO-CAM model 617b481400000389 is a high-quality representation of the role of KAT5/TIP60 in regulating mitotic processes through protein acetylation. It accurately captures the interplay between KAT5, AURKB, SIRT1, and NDC80 during mitosis, supported by strong experimental evidence. The model demonstrates how acetylation and deacetylation events regulate protein function during mitotic sister chromatid segregation and kinetochore-microtubule attachment. The model is consistent with GO-CAM best practices and presents a coherent regulatory pathway.