Closing in on the resting state of the Shaker K(+) channel.
Membrane depolarization causes voltage-gated ion channels to transition from a resting/closed conformation to an activated/open conformation. We used voltage-clamp fluorometry to measure protein motion at specific regions of the Shaker Kv channel. This enabled us to construct new structural models of the resting/closed and activated/open states based on the Kv1.2 crystal structure using the Rosetta-Membrane method and molecular dynamics simulations. Our models account for the measured gating charge displacement and suggest a molecular mechanism of activation in which the primary voltage sensors, S4s, rotate by approximately 180 degrees as they move "outward" by 6-8 A. A subsequent tilting motion of the S4s and the pore domain helices, S5s, of all four subunits induces a concerted movement of the channel's S4-S5 linkers and S6 helices, allowing ion conduction. Our models are compatible with a wide body of data and resolve apparent contradictions that previously led to several distinct models of voltage sensing.
Pathak
Medha M
MM
Biophysics Graduate Program, University of California Berkeley, Berkeley, CA 94720, USA.
Yarov-Yarovoy
Vladimir
V
Agarwal
Gautam
G
Roux
Benoît
B
Barth
Patrick
P
Kohout
Susy
S
Tombola
Francesco
F
Isacoff
Ehud Y
EY
D000818:Animals; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation; D015640:Ion Channel Gating / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology* / Q000528:radiation effects; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation / Q000502:physiology; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051637:Shaker Superfamily of Potassium Channels / Q000502:physiology*; D013329:Structure-Activity Relationship
D051637:Shaker Superfamily of Potassium Channels