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<i>In silico</i> models of the macromolecular Na<sub>V</sub>1.5-K<sub>IR</sub>2.1 complex.

ABSTRACT: In cardiac cells, the expression of the cardiac voltage-gated Na+ channel (NaV1.5) is reciprocally regulated with the inward rectifying K+ channel (KIR2.1). These channels can form macromolecular complexes that pre-assemble early during forward trafficking (transport to the cell membrane). In this study, we present in silico 3D models of NaV1.5-KIR2.1, 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 KIR2.1 and NaV1.5 malfunctions.

SUBMITTER: Stary-Weinzinger A 

PROVIDER: S-EPMC10925717 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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&lt;i&gt;In silico&lt;/i&gt; models of the macromolecular Na&lt;sub&gt;V&lt;/sub&gt;1.5-K&lt;sub&gt;IR&lt;/sub&gt;2.1 complex.

Stary-Weinzinger Anna A  

Frontiers in physiology 20240226

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 <i>in silico</i> 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 learni  ...[more]

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