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Mechanistic insights into the interaction of the MOG1 protein with the cardiac sodium channel Nav1.5 clarify the molecular basis of Brugada syndrome
- Source :
- Journal of Biological Chemistry. 293:18207-18217
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Na(v)1.5 is the α-subunit of the cardiac sodium channel complex. Abnormal expression of Na(v)1.5 on the cell surface because of mutations that disrupt Na(v)1.5 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(v)1.5, promotes Na(v)1.5 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(v)1.5. Large deletion analysis mapped the MOG1 domain required for the interaction with Na(v)1.5 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(v)1.5. GST pulldown and electrophysiological analyses disclosed that the substitutions E83D, D148Q, R150Q, and S151Q disrupt MOG1's interaction with Na(v)1.5 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(v)1.5. In conclusion, our findings identify the structural elements in MOG1 that are crucial for its interaction with Na(v)1.5 and improve our understanding of how the E83D substitution causes BrS.
- Subjects :
- 0301 basic medicine
Amino Acid Motifs
Mutation, Missense
030204 cardiovascular system & hematology
Nav1.5
Biochemistry
NAV1.5 Voltage-Gated Sodium Channel
Protein–protein interaction
03 medical and health sciences
0302 clinical medicine
Protein Domains
Cardiac conduction
medicine
Humans
Myocytes, Cardiac
Binding site
Molecular Biology
Brugada Syndrome
Brugada syndrome
biology
Chemistry
Sodium channel
Molecular Bases of Disease
Cell Biology
Sudden infant death syndrome
medicine.disease
Cell biology
Protein Transport
ran GTP-Binding Protein
030104 developmental biology
Amino Acid Substitution
Sodium channel complex
biology.protein
Gene Deletion
Protein Binding
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 293
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....781347a00695a187cae5ae6d0d744d71