A specificity map for the PDZ domain family.

Area of Science:

• Molecular Biology
• Proteomics
• Structural Biology

Background:

• PDZ domains are key protein-protein interaction modules.
• They recognize specific C-terminal sequences to form protein complexes.
• Understanding PDZ domain specificity is vital for cell biology and disease research.

Purpose of the Study:

• To comprehensively map the binding specificities of human and C. elegans PDZ domains.
• To identify conserved specificity classes and extend the known classification system.
• To investigate the robustness and evolutionary potential of PDZ domain binding sites.

Main Methods:

• Large-scale scanning of billions of random peptides to profile PDZ domain binding.
• Specificity profiling of 91 point mutants of a model PDZ domain.
• Prediction and experimental validation of viral PDZ domain ligands.

Main Results:

• Accurate binding specificity maps were generated for approximately half of human and C. elegans PDZ domains.
• Sixteen distinct specificity classes were identified, conserved from worms to humans, expanding the canonical two-class system.
• PDZ domain binding sites are robust, yet mutations can rapidly alter specificity, suggesting rapid evolution.
• Viral ligands targeting PDZ domains involved in cell polarity and growth were predicted and validated.

Conclusions:

• Most PDZ domains exhibit fine-tuned, specific interactions rather than promiscuity.
• Specificity profiling provides a powerful tool for predicting and prioritizing protein interactions.
• Viruses exploit PDZ domain interactions to disrupt host cell processes, with pathogenic strains targeting critical pathways.