Mechanistic insights into the interaction of the MOG1 protein with the cardiac sodium channel Na_v1.5 clarify the molecular basis of Brugada syndrome.

Na_v1.5 is the α-subunit of the cardiac sodium channel complex. Abnormal expression of Na_v1.5 on the cell surface because of mutations that disrupt Na_v1.5 trafficking causes Brugada syndrome (BrS), sick sinus syndrome (SSS), cardiac conduction disease, dilated cardiomyopathy, and sudden infant death syndrome. We and others previously reported that Ran-binding protein MOG1 (MOG1), a small protein that interacts with Na_v1.5, promotes Na_v1.5 intracellular trafficking to plasma membranes and that a substitution in MOG1, E83D, causes BrS. However, the molecular basis for the MOG1/Nav1.5 interaction and how the E83D substitution causes BrS remains unknown. Here, we assessed the effects of defined MOG1 deletions and alanine-scanning substitutions on MOG1's interaction with Na_v1.5. Large deletion analysis mapped the MOG1 domain required for the interaction with Na_v1.5 to the region spanning amino acids 146-174, and a refined deletion analysis further narrowed this domain to amino acids 146-155. Site-directed mutagenesis further revealed that Asp-148, Arg-150, and Ser-151 cluster in a peptide loop essential for binding to Na_v1.5. GST pulldown and electrophysiological analyses disclosed that the substitutions E83D, D148Q, R150Q, and S151Q disrupt MOG1's interaction with Na_v1.5 and significantly reduce its trafficking to the cell surface. Examination of MOG1's 3D structure revealed that Glu-83 and the loop containing Asp-148, Arg-150, and Ser-151 are spatially proximal, suggesting that these residues form a critical binding site for Na_v1.5. In conclusion, our findings identify the structural elements in MOG1 that are crucial for its interaction with Na_v1.5 and improve our understanding of how the E83D substitution causes BrS.

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