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)
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.
Trita-FYS, ISSN 0280-316X ; 2011:29
activation, deactivation, inactivation, voltage-sensor, VSD, Kv1.2- 2.1, F233, hydrophobic barrier, alpha-helix, 3(10)-helix
Condensed Matter Physics
IdentifiersURN: urn:nbn:se:kth:diva-33818ISBN: 978-91-7501-041-0OAI: oai:DiVA.org:kth-33818DiVA: diva2:417956
2011-06-15, Sal FA31, Roslagstullsbacken 21, AlbaNova, Stockholm, 15:00
Kamerlin, Lynn, Ass. professor
Lindahl, Erik, Professor
QC 201106162011-06-162011-05-192011-06-16Bibliographically approved
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