S1 Constrains S4 in the Voltage Sensor Domain of Kv7.1 K+ Channels

Voltage-gated K+ channels comprise a central pore enclosed by four voltage-sensing domains (VSDs). While movement of the S4 helix is known to couple to channel gate opening and closing, the nature of S4 motion is unclear. Here, we substituted S4 residues of Kv7.1 channels by cysteine and recorded whole-cell mutant channel currents in Xenopus oocytes using the two-electrode voltage-clamp technique. In the closed state, disulfide and metal bridges constrain residue S225 (S4) nearby C136 (S1) within the same VSD. In the open state, two neighboring I227 (S4) are constrained at proximity while residue R228 (S4) is confined close to C136 (S1) of an adjacent VSD. Structural modeling predicts that in the closed to open transition, an axial rotation (∼190°) and outward translation of S4 (∼12 Å) is accompanied by VSD rocking. This large sensor motion changes the intra-VSD S1–S4 interaction to an inter-VSD S1–S4 interaction. These constraints provide a ground for cooperative subunit interactions and suggest a key role of the S1 segment in steering S4 motion during Kv7.1 gating.

[1]  Roderick MacKinnon,et al.  Contribution of the S4 Segment to Gating Charge in the Shaker K+ Channel , 1996, Neuron.

[2]  Francisco Bezanilla,et al.  Voltage-Sensing Residues in the S2 and S4 Segments of the Shaker K+ Channel , 1996, Neuron.

[3]  R. Horn,et al.  Probing the outer vestibule of a sodium channel voltage sensor. , 1997, Biophysical journal.

[4]  R. Aldrich,et al.  Mutations in the S4 Region Isolate the Final Voltage-dependent Cooperative Step in Potassium Channel Activation , 1999, The Journal of general physiology.

[5]  Ehud Y. Isacoff,et al.  Independence and Cooperativity in Rearrangements of a Potassium Channel Voltage Sensor Revealed by Single Subunit Fluorescence , 2000, The Journal of general physiology.

[6]  C. Partridge,et al.  Depolarization Induces Intersubunit Cross-linking in a S4 Cysteine Mutant of the Shaker Potassium Channel* , 2002, The Journal of Biological Chemistry.

[7]  E. Isacoff,et al.  Molecular Models of Voltage Sensing , 2002, The Journal of general physiology.

[8]  R. Horn,et al.  Movement and Crevices Around a Sodium Channel S3 Segment , 2002, The Journal of general physiology.

[9]  B. Attali,et al.  External Barium Affects the Gating of KCNQ1 Potassium Channels and Produces a Pore Block via Two Discrete Sites , 2004, The Journal of general physiology.

[10]  R. Horn,et al.  Stirring up controversy with a voltage sensor paddle , 2004, Trends in Neurosciences.

[11]  F. Bezanilla,et al.  A proton pore in a potassium channel voltage sensor reveals a focused electric field , 2004, Nature.

[12]  David J. S. Elliott,et al.  Molecular mechanism of voltage sensor movements in a potassium channel , 2004, The EMBO journal.

[13]  J. Nerbonne,et al.  Molecular physiology of cardiac repolarization. , 2005, Physiological reviews.

[14]  E. Campbell,et al.  Crystal Structure of a Mammalian Voltage-Dependent Shaker Family K+ Channel , 2005, Science.

[15]  Roderick MacKinnon,et al.  Calibrated Measurement of Gating-Charge Arginine Displacement in the KvAP Voltage-Dependent K+ Channel , 2005, Cell.

[16]  Ehud Isacoff,et al.  The Cooperative Voltage Sensor Motion that Gates a Potassium Channel , 2005, The Journal of general physiology.

[17]  E. Isacoff,et al.  Voltage-Sensing Arginines in a Potassium Channel Permeate and Occlude Cation-Selective Pores , 2005, Neuron.

[18]  J. Mindell,et al.  Voltage-sensor activation with a tarantula toxin as cargo , 2005, Nature.

[19]  David Baker,et al.  Voltage sensor conformations in the open and closed states in ROSETTA structural models of K(+) channels. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Ehud Y Isacoff,et al.  How does voltage open an ion channel? , 2006, Annual review of cell and developmental biology.

[21]  Francisco Bezanilla,et al.  Two atomic constraints unambiguously position the S4 segment relative to S1 and S2 segments in the closed state of Shaker K channel , 2007, Proceedings of the National Academy of Sciences.

[22]  A. A. Alabi,et al.  Portability of paddle motif function and pharmacology in voltage sensors , 2007, Nature.

[23]  Structure prediction for the down state of a potassium channel voltage sensor , 2007, Nature.

[24]  E. Campbell,et al.  Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment , 2007, Nature.

[25]  E. Isacoff,et al.  The twisted ion-permeation pathway of a resting voltage-sensing domain , 2007, Nature.

[26]  B. Attali,et al.  An inactivation gate in the selectivity filter of KCNQ1 potassium channels. , 2007, Biophysical journal.