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Tracking a complete voltage-sensor cycle with metal-ion bridges
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2012 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 22, 8552-8557 p.Article in journal (Refereed) Published
Abstract [en]

Voltage-gated ion channels open and close in response to changes in membrane potential, thereby enabling electrical signaling in excitable cells. The voltage sensitivity is conferred through four voltage-sensor domains (VSDs) where positively charged residues in the fourth transmembrane segment (S4) sense the potential. While an open state is known from the Kv1.2/2.1 X-ray structure, the conformational changes underlying voltage sensing have not been resolved. We present 20 additional interactions in one open and four different closed conformations based on metal-ion bridges between all four segments of the VSD in the voltage-gated Shaker K channel. A subset of the experimental constraints was used to generate Rosetta models of the conformations that were subjected to molecular simulation and tested against the remaining constraints. This achieves a detailed model of intermediate conformations during VSD gating. The results provide molecular insight into the transition, suggesting that S4 slides at least 12 angstrom along its axis to open the channel with a 3(10) helix region present that moves in sequence in S4 in order to occupy the same position in space opposite F290 from open through the three first closed states.

Place, publisher, year, edition, pages
2012. Vol. 109, no 22, 8552-8557 p.
Keyword [en]
electrophysiology, inactivation, Xenopus oocytes, voltage clamp, conformational transition
National Category
Other Physics Topics
URN: urn:nbn:se:kth:diva-98329DOI: 10.1073/pnas.1116938109ISI: 000304881700044ScopusID: 2-s2.0-84861838905OAI: diva2:536934
Swedish Research CouncilEU, European Research CouncilSwedish e‐Science Research CenterScience for Life Laboratory - a national resource center for high-throughput molecular bioscience

QC 20120625

Available from: 2012-06-25 Created: 2012-06-25 Last updated: 2013-04-15Bibliographically approved
In thesis
1. Voltage sensor activation and modulation in ion channels
Open this publication in new window or tab >>Voltage sensor activation and modulation in ion channels
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Voltage-gated ion channels play fundamental roles in neural excitability, they are for instance responsible for every single heart beat in our bodies, and dysfunctional channels cause disease that can be even lethal. Understanding how the voltage sensor of these channels function is critical for drug design of compounds targeting neuronal excitability.

The opening and closing of the pore in voltage-gated potassium (Kv) channels is caused by the arginine-rich S4 helix of the voltage sensor domain (VSD) moving in response to an external potential. In fact, VSDs are remarkably efficient at turning membrane potential into conformational changes, which likely makes them the smallest existing biological engines. Exactly how this is accomplished is not yet fully known and an area of hot debate, especially due to the lack of structures of the resting and intermediate states along the activation pathway. In this thesis I study how the VSD activation works and show how toxic compounds modulate channel gating through direct interaction with these quite unexplored drug targets.

First, I show that a secondary structure transition from alpha- to 3(10)-helix in the S4 helix is an important part of the gating as this helix type is significantly more favorable compared to the -helix in terms of a lower free energy barrier. Second, I present new models for intermediate states along the whole voltage sensor cycle from closed to open and suggest a new gating model for S4, where it moves as a sliding 3(10)-helix. Interestingly, this 3(10)-helix is formed in the region of the single most conserved residue in Kv channels, the phenylalanine F233. Located in the hydrophobic core, it directly faces S4 and creates a structural barrier for the gating charges. Substituting this residue alters the deactivation free energy barrier and can either facilitate the relaxation of the voltage sensor or increase the free energy barrier, depending on the size of the mutant. These results are confirmed by new experimental data that supports that a rigid ring at the phenylalanine position is the rate-limiting factor for the deactivation gating process, while the activation is unaffected. Finally, we study how the activation can be modulated for pharmaceutical reasons. Neurotoxins such as hanatoxin and stromatoxin push S3b towards S4 helix limiting S4's flexibility. This makes it harder for the VSD to activate and might explain the stronger binding affinities in resting state.

All these results are highly important both for the general topic of biological macromolecules undergoing functionally critical conformational transitions, as well as the particular case of voltage-gated ion channels where understanding of the gating process is probably the key step to explain the effects of mutations or drug interactions.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2012. xiii, 77 p.
Trita-FYS, ISSN 0280-316X ; 2012:77
activation, deactivation, inactivation, voltage sensor, VSD, gating, Kv1.2-2.1, Shaker, F233, hydrophobic barrier
National Category
Biological Sciences
urn:nbn:se:kth:diva-104742 (URN)978-91-7501-498-2 (ISBN)
Public defence
2012-12-07, FB53, AlbaNova universitetscentrum, Stockholm, 10:00 (English)
Swedish e‐Science Research CenterScience for Life Laboratory - a national resource center for high-throughput molecular bioscience

QC 20121115

Available from: 2012-11-15 Created: 2012-11-09 Last updated: 2013-04-15Bibliographically approved

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Schwaiger, Christine S.Bjelkmar, PärLindahl, Erik
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