AUTHOR=Stary-Weinzinger Anna 

TITLE=In silico models of the macromolecular NaV1.5-KIR2.1 complex

JOURNAL=Frontiers in Physiology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2024.1362964

DOI=10.3389/fphys.2024.1362964

ISSN=1664-042X

ABSTRACT=<p>In cardiac cells, the expression of the cardiac voltage-gated Na<sup>+</sup> channel (Na<sub>V</sub>1.5) is reciprocally regulated with the inward rectifying K<sup>+</sup> channel (K<sub>IR</sub>2.1). These channels can form macromolecular complexes that pre-assemble early during forward trafficking (transport to the cell membrane). In this study, we present <italic>in silico</italic> 3D models of Na<sub>V</sub>1.5-K<sub>IR</sub>2.1, generated by rigid-body protein-protein docking programs and deep learning-based AlphaFold-Multimer software. Modeling revealed that the two channels could physically interact with each other along the entire transmembrane region. Structural mapping of disease-associated mutations revealed a hotspot at this interface with several trafficking-deficient variants in close proximity. Thus, examining the role of disease-causing variants is important not only in isolated channels but also in the context of macromolecular complexes. These findings may contribute to a better understanding of the life-threatening cardiovascular diseases underlying K<sub>IR</sub>2.1 and Na<sub>V</sub>1.5 malfunctions.</p>