Outlining cardiac ion channel protein interactors and their signature in the human electrocardiogram

Abstract Protein–protein interactions are essential for normal cellular processes and signaling events. Defining these interaction networks is therefore crucial understanding complex functions interpretation of disease-associated gene variants. We need to build a comprehensive picture the interactions, their affinities interdependencies in specific organ decipher hitherto poorly understood mechanisms through ion channels. Here we report experimental identification ensemble protein interactors 13 types channels murine cardiac tissue. Of these, validated functional importance ten on electrophysiology genetic knockouts zebrafish, silencing mice, super-resolution microscopy patch clamp experiments. Furthermore, establish computational framework reconstruct human cardiomyocyte channel from deep proteome mapping heart tissue single-cell expression data. Finally, integrate interactome with population genetics data identify proteins that influence electrocardiogram (ECG). demonstrate combined network enriched influencing ECG, 44% significantly associated an ECG phenotype. Altogether, define interactomes major channels, contextualize relevance validate roles interactors, including two regulators sodium current (epsin-2 gelsolin). Overall, our provide roadmap molecular machinery regulates electrophysiology.