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Assessing the role and potential pathogenicity of protein variants by quantitative interactomics

Human Health Proteomics Peptidomics and small proteins

Abstract #34 Posted on24 February 202529 April 2025 29 April 2025 10h20

Abstract

To assess the role and potential pathogenicity of protein variants in modulating protein-protein interaction (PPI) networks we focused on the PDZ domain family in signal proteins. The human proteome contains 266 PDZ domains and more than 4,000 PDZ binding motifs (PBM). PDZ-PBM interaction networks regulate multiple biological processes such as transport, cell signalling, cell polarity, etc. Functional perturbations in these networks can cause the development of cancers, degenerations of the nervous system and other diseases.

We designed 52 different PDZ single variants from disease-associated variants and human natural polymorphisms with different allele frequencies. Then we utilised the high-throughput Holdup assay, developed by our group, to measure PPI affinities (Kd) at an unprecedented scale and precision, quantifying over 20,000 interactions between wt and variant PDZ-PBM pairs, with more than 4,000 Kd values detected. Different types of interactome perturbations were observed, such as unaffected, destabilised and reshuffled interactomes. Furthermore, these interactome perturbations depended on the variant categories: likely pathogenic vs. likely benign variants and (binding) interfacial vs. non-interfacial variants.

The long-term plan of this project is to further understand the impact of single variants on cell activities through understanding the impact of single variants on PPI networks, and ultimately describe pathogenic mechanisms with better precision.

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We designed 52 different PDZ single variants from disease-associated variants and human natural polymorphisms with different allele frequencies. Then we utilised the high-throughput Holdup assay, developed by our group, to measure PPI affinities (Kd) at an unprecedented scale and precision, quantifying over 20,000 interactions between wt and variant PDZ-PBM pairs, with more than 4,000 Kd values detected. Different types of interactome perturbations were observed, such as unaffected, destabilised and reshuffled interactomes. Furthermore, these interactome perturbations depended on the variant categories: likely pathogenic vs. likely benign variants and (binding) interfacial vs. non-interfacial variants.

The long-term plan of this project is to further understand the impact of single variants on cell activities through understanding the impact of single variants on PPI networks, and ultimately describe pathogenic mechanisms with better precision.

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