Pathogenic mutations of human phosphorylation sites affect protein–protein interactions

Trendelina Rrustemi, Katrina Meyer, Yvette Roske, Bora Uyar, Altuna Akalin, Koshi Imami, Yasushi Ishihama, Oliver Daumke and Matthias Selbach ()
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Trendelina Rrustemi: Max Delbrück Center (MDC)
Katrina Meyer: Max Delbrück Center (MDC)
Yvette Roske: Max Delbrück Center (MDC)
Bora Uyar: Max Delbrück Center (MDC)
Altuna Akalin: Max Delbrück Center (MDC)
Koshi Imami: Kyoto University
Yasushi Ishihama: Kyoto University
Oliver Daumke: Max Delbrück Center (MDC)
Matthias Selbach: Max Delbrück Center (MDC)

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46794-8

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