8Q1S

Pathogenic mutations of human phosphorylation sites affect protein-protein interactions

Summary for 8Q1S

• Entry DOI: 10.2210/pdb8q1s/pdb
• Descriptor: 14-3-3 protein epsilon, GATA zinc finger domain-containing protein 1, BROMIDE ION, ... (6 entities in total)
• Functional Keywords: 14-3-3, gatad1, protein-protein interaction, peptide binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 62224.80

Authors

Roske, Y.,Daumke, O.,Rrustemi, T.,Selbach, M. (deposition date: 2023-08-01, release date: 2024-02-21, Last modification date: 2024-04-24)

Primary citation

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.
Nat Commun, 15:3146-3146, 2024

PubMed 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.

PubMed: 38605029
DOI: 10.1038/s41467-024-46794-8

Experimental method

X-RAY DIFFRACTION (3.23 Å)