Effect of sensor domain mutations on the properties of voltage-gated ion channels: molecular dynamics studies of the potassium channel Kv1.2.
The effects on the structural and functional properties of the Kv1.2 voltage-gated ion channel, caused by selective mutation of voltage sensor domain residues, have been investigated using classical molecular dynamics simulations. Following experiments that have identified mutations of voltage-gated ion channels involved in state-dependent omega currents, we observe for both the open and closed conformations of the Kv1.2 that specific mutations of S4 gating-charge residues destabilize the electrostatic network between helices of the voltage sensor domain, resulting in the formation of hydrophilic pathways linking the intra- and extracellular media. When such mutant channels are subject to transmembrane potentials, they conduct cations via these so-called "omega pores." This study provides therefore further insight into the molecular mechanisms that lead to omega currents, which have been linked to certain channelopathies.
UMR 7565, Structure et Réactivité des Systèmes Moléculaires Complexes, Centre National de Recherche Scientifique-Nancy University, Nancy cedex, France.
Lucie
L
Delemotte
Werner
W
Treptow
Michael L
ML
Klein
Mounir
M
Tarek
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D055592:Biophysical Phenomena; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D051663:Kv1.2 Potassium Channel / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008564:Membrane Potentials; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity
D051663:Kv1.2 Potassium Channel; D050505:Mutant Proteins