Mapping Dysfunctional Protein-Protein Interactions in Disease.

Area of Science:

• Systems Biology
• Chemoproteomics
• Network Biology

Background:

• Protein-protein interaction (PPI) networks are crucial in disease but often studied by protein abundance changes, neglecting interaction dysfunction.
• Current systems biology approaches overlook critical interaction-level dysfunction in disease progression.

Purpose of the Study:

• To introduce a robust chemoproteomic method, dysfunctional Protein-Protein Interactome (dfPPI), for high-throughput, disease-contextual mapping of PPI network dysfunctions.
• To enable systematic identification of rewiring in protein networks that are not apparent from transcriptomic or proteomic data alone.

Main Methods:

• Integration of chemical biology probes to capture epichaperome-based interactome assemblies.
• Label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) for proteomic analysis.
• Network-based computational analysis to uncover PPI network rewiring.

Main Results:

• The dfPPI platform successfully maps PPI network dysfunctions in cells and primary human tissues.
• Identified rewiring of protein networks not detectable by transcriptomic or proteomic analyses.
• Demonstrated applicability across disease states, species, and tissues.

Conclusions:

• The dfPPI method provides a powerful tool for identifying actionable nodes of dysfunction in disease.
• Enables high-resolution, systems-level insights into disease progression and network rewiring.
• Promotes reproducibility and accessibility for broader adoption in systems biology and translational research.