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Pathogenic mutations of human phosphorylation sites affect protein–protein interactions

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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
Publisher:Nature Publishing Group
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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