Pathogenic mutations of human phosphorylation sites affect protein–protein interactions

Rrustemi, T.; Meyer, K.; Roske, Y.; Uyar, B.; Akalin, A.; Imami, K.; Ishihama, Y.; Daumke, O.; Selbach, M.

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., Meyer, K., Roske, Y., Uyar, B., Akalin, A., Imami, K., Ishihama, Y., 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

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