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Modulation of the voltage sensor resting state through Hanatoxin and Stromatoxin
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical & Computational Biophysics.
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(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:kth:diva-104740OAI: oai:DiVA.org:kth-104740DiVA: diva2:566862
Note

QS 2012

Available from: 2012-11-09 Created: 2012-11-09 Last updated: 2016-08-16Bibliographically 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.
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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Lindahl, Erik

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