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| Item Type: | Article |
|---|---|
| Title: | Pathogenic mutations of human phosphorylation sites affect protein–protein interactions |
| Creators: |
Rrustemi, T.  ORCID: https://orcid.org/0000-0002-9075-103X, Meyer, K. ORCID: https://orcid.org/0000-0002-8244-6887, Roske, Y. ORCID: https://orcid.org/0000-0001-6237-388X, Uyar, B. ORCID: https://orcid.org/0000-0002-3170-4890, Akalin, A. ORCID: https://orcid.org/0000-0002-0468-0117, Imami, K. ORCID: https://orcid.org/0000-0002-7451-4982, Ishihama, Y., Daumke, O. ORCID: https://orcid.org/0000-0002-6190-1414 and Selbach, M. ORCID: https://orcid.org/0000-0003-2454-8751
|
| Abstract: | Despite their lack of a defined 3D structure, intrinsically disordered regions (IDRs) of proteins play important biological roles. Many IDRs contain short linear motifs (SLiMs) that mediate protein-protein interactions (PPIs), which can be regulated by post-translational modifications like phosphorylation. 20% of pathogenic missense mutations are found in IDRs, and understanding how such mutations affect PPIs is essential for unraveling disease mechanisms. Here, we employ peptide-based interaction proteomics to investigate 36 disease-associated mutations affecting phosphorylation sites. Our results unveil significant differences in interactomes between phosphorylated and non-phosphorylated peptides, often due to disrupted phosphorylation-dependent SLiMs. We focused on a mutation of a serine phosphorylation site in the transcription factor GATAD1, which causes dilated cardiomyopathy. We find that this phosphorylation site mediates interaction with 14-3-3 family proteins. Follow-up experiments reveal the structural basis of this interaction and suggest that 14-3-3 binding affects GATAD1 nucleocytoplasmic transport by masking a nuclear localisation signal. Our results demonstrate that pathogenic mutations of human phosphorylation sites can significantly impact protein-protein interactions, offering insights into potential molecular mechanisms underlying pathogenesis. |
| Keywords: | Intrinsically Disordered Proteins, Phosphorylation, Protein–Protein Interaction Networks |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 15 |
| Number: | 1 |
| Page Range: | 3146 |
| Date: | 11 April 2024 |
| Official Publication: | https://doi.org/10.1038/s41467-024-46794-8 |
| PubMed: | View item in PubMed |
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