Models of voltage-dependent conformational changes in NaChBac channels.
Models of the transmembrane region of the NaChBac channel were developed in two open/inactivated and several closed conformations. Homology models of NaChBac were developed using crystal structures of Kv1.2 and a Kv1.2/2.1 chimera as templates for open conformations, and MlotiK and KcsA channels as templates for closed conformations. Multiple molecular-dynamic simulations were performed to refine and evaluate these models. A striking difference between the S4 structures of the Kv1.2-like open models and MlotiK-like closed models is the secondary structure. In the open model, the first part of S4 forms an alpha-helix, and the last part forms a 3(10) helix, whereas in the closed model, the first part of S4 forms a 3(10) helix, and the last part forms an alpha-helix. A conformational change that involves this type of transition in secondary structure should be voltage-dependent. However, this transition alone is not sufficient to account for the large gating charge movement reported for NaChBac channels and for experimental results in other voltage-gated channels. To increase the magnitude of the motion of S4, we developed another model of an open/inactivated conformation, in which S4 is displaced farther outward, and a number of closed models in which S4 is displaced farther inward. A helical screw motion for the alpha-helical part of S4 and a simple axial translation for the 3(10) portion were used to develop models of these additional conformations. In our models, four positively charged residues of S4 moved outwardly during activation, across a transition barrier formed by highly conserved hydrophobic residues on S1, S2, and S3. The S4 movement was coupled to an opening of the activation gate formed by S6 through interactions with the segment linking S4 to S5. Consistencies of our models with experimental studies of NaChBac and K(v) channels are discussed.
Shafrir
Yinon
Y
Laboratory of Cell Biology, CCR, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-5567, USA.
Durell
Stewart R
SR
Guy
H Robert
HR
D001360:Avidin / Q000737:chemistry; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism*; D001710:Biotin / Q000737:chemistry; D031541:Fluorescence Resonance Energy Transfer; D015640:Ion Channel Gating; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry; D016415:Sequence Alignment; D051637:Shaker Superfamily of Potassium Channels / Q000737:chemistry; D015222:Sodium Channels / Q000737:chemistry* / Q000378:metabolism*
D001426:Bacterial Proteins; C443666:NaChBac protein, bacteria; D021122:Protein Subunits; D051637:Shaker Superfamily of Potassium Channels; D015222:Sodium Channels; D001360:Avidin; D001710:Biotin