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310-Helix Conformation Facilitates the Transition of a Voltage Sensor S4 Segment toward the Down State
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics. (Theoretical and Computational Biophysics)
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.ORCID iD: 0000-0002-7498-7763
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.ORCID iD: 0000-0002-2734-2794
2011 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 100, no 6, 1446-1454 p.Article in journal (Refereed) Published
Abstract [en]

The activation of voltage-gated ion channels is controlled by the S4 helix, with arginines every third residue. The x-ray structures are believed to reflect an open-inactivated state, and models propose combinations of translation, rotation, and tilt to reach the resting state. Recently, experiments and simulations have independently observed occurrence of 3(10)-helix in S4. This suggests S4 might make a transition from alpha- to 3(10)-helix in the gating process. Here, we show 3(10)-helix structure between 01 and R3 in the S4 segment of a voltage sensor appears to facilitate the early stage of the motion toward a down state. We use multiple microsecond-steered molecular simulations to calculate the work required for translating S4 both as a-helix and transformed to 3(10)-helix. The barrier appears to be caused by salt-bridge reformation simultaneous to R4 passing the F233 hydrophobic lock, and it is almost a factor-two lower with 3(10)-helix. The latter facilitates translation because R2/R3 line up to face E183/E226, which reduces the requirement to rotate S4. This is also reflected in a lower root mean-square deviation distortion of the rest of the voltage sensor. This supports the 3(10) hypothesis, and could explain some of the differences between the open-inactivated- versus activated-states.

Place, publisher, year, edition, pages
2011. Vol. 100, no 6, 1446-1454 p.
National Category
Biophysics Bioinformatics and Systems Biology Theoretical Chemistry
Research subject
SRA - E-Science (SeRC)
Identifiers
URN: urn:nbn:se:kth:diva-33480DOI: 10.1016/j.bpj.2011.02.003ISI: 000288889700008Scopus ID: 2-s2.0-79953898210OAI: oai:DiVA.org:kth-33480DiVA: diva2:417191
Funder
EU, European Research Council, 209825Swedish Research CouncilSwedish e‐Science Research Center
Note

QC 20150716

Available from: 2011-05-16 Created: 2011-05-09 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Dynamics of the voltage-sensor domain in voltage-gated ion channels: Studies on helical content and hydrophobic barriers within voltage-sensor domains
Open this publication in new window or tab >>Dynamics of the voltage-sensor domain in voltage-gated ion channels: Studies on helical content and hydrophobic barriers within voltage-sensor domains
2011 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Voltage-gated ion channels play fundamental roles in neural excitability and thus dysfunctional channels can cause disease. Understanding how the voltage-sensor of these channels activate and inactivate could potentially be useful in future drug design of compounds targeting neuronal excitability.

The opening and closing of the pore in voltage-gated ion channels is caused by the arginine-rich S4 helix of the voltage sensor domain (VSD) moving in response to an external potential. Exactly how this movement is accomplished is not yet fully known and an area of hot debate. In this thesis I study how the opening and closing in voltage-gated potassium (Kv) channels occurs.

Recently, both experimental and computational results have pointed to the possibility of a secondary structure transition from α- to 3(10)-helix in S4 being an important part of the gating. First, I show that the 3(10)-helix structure in the S4 helix of a Kv1.2-2.1 chimera protein is significantly more favorable compared to the α-helix in terms of a lower free energy barrier during the gating motion. Additional I suggest a new gating model for S4, moving as sliding 310-helix. Interestingly, the single most conserved residue in voltage- gated ion channels is a phenylalanine located in the hydrophobic core and directly facing S4 causing a barrier for the gating charges.

In a second study, I address the problem of the energy barrier and show that mutations of the phenylalanine directly alter the free energy barrier of the open to closed transition for S4. Mutations 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, cyclic ring at the phenylalanine position is the determining rate-limiting factor for the voltage sensor gating process.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2011. xi, 61 p.
Series
Trita-FYS, ISSN 0280-316X ; 2011:29
Keyword
activation, deactivation, inactivation, voltage-sensor, VSD, Kv1.2- 2.1, F233, hydrophobic barrier, alpha-helix, 3(10)-helix
National Category
Condensed Matter Physics
Identifiers
urn:nbn:se:kth:diva-33818 (URN)978-91-7501-041-0 (ISBN)
Presentation
2011-06-15, Sal FA31, Roslagstullsbacken 21, AlbaNova, Stockholm, 15:00
Opponent
Supervisors
Note
QC 20110616Available from: 2011-06-16 Created: 2011-05-19 Last updated: 2011-06-16Bibliographically approved
2. 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.
Series
Trita-FYS, ISSN 0280-316X ; 2012:77
Keyword
activation, deactivation, inactivation, voltage sensor, VSD, gating, Kv1.2-2.1, Shaker, F233, hydrophobic barrier
National Category
Biological Sciences
Identifiers
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)
Opponent
Supervisors
Funder
Swedish e‐Science Research CenterScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20121115

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

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