![[feed]](/style/images/feed-icon-14x14.png){kind=icon}
|
PDF (Original Article)
- Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
2MB | |
![[img]](http://edoc.mdc-berlin.de/style/images/fileicons/other.png) |
Other (Supporting Information)
62MB |
| Item Type: | Article |
|---|---|
| Title: | Pathogenic mutations of human phosphorylation sites affect protein–protein interactions |
| Creators Name: | Rrustemi, T. and Meyer, K. and Roske, Y. and Uyar, B. and Akalin, A. and Imami, K. and Ishihama, Y. and Daumke, O. and Selbach, M. |
| 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 |
Repository Staff Only: item control page
Download Statistics
Download Statistics
