S4-S5 Linker Movement During Activation and Inactivation in Voltage-gated K Channels

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2018 Jul 1

PMID 29959207

Citations 33

Authors

Tanja Kalstrup

Rikard Blunck

Affiliations

Soon will be listed here.

Abstract

The S4-S5 linker physically links voltage sensor and pore domain in voltage-gated ion channels and is essential for electromechanical coupling between both domains. Little dynamic information is available on the movement of the cytosolic S4-S5 linker due to lack of a direct electrical or optical readout. To understand the movements of the gating machinery during activation and inactivation, we incorporated fluorescent unnatural amino acids at four positions along the linker of the Shaker K channel. Using two-color voltage-clamp fluorometry, we compared S4-S5 linker movements with charge displacement, S4 movement, and pore opening. We found that the proximal S4-S5 linker moves with the S4 helix throughout the gating process, whereas the distal portion undergoes a separate motion related to late gating transitions. Both pore and S4-S5 linker undergo rearrangements during C-type inactivation. In presence of accelerated C-type inactivation, the energetic coupling between movement of the distal S4-S5 linker and pore opening disappears.

Citing Articles

Genetic Code Expansion: Recent Developments and Emerging Applications.

Huang Y, Zhang P, Wang H, Chen Y, Liu T, Luo X Chem Rev. 2024; 125(2):523-598.

PMID: 39737807 PMC: 11758808. DOI: 10.1021/acs.chemrev.4c00216.

Voltage-clamp fluorometry for advancing mechanistic understanding of ion channel mechanisms with a focus on acid-sensing ion channels.

Centonze E, Kellenberger S Biochem Soc Trans. 2024; 52(5):2167-2177.

PMID: 39400205 PMC: 11555705. DOI: 10.1042/BST20240165.

Genetic Code Expansion for Mechanistic Studies in Ion Channels: An (Un)natural Union of Chemistry and Biology.

Infield D, Schene M, Galpin J, Ahern C Chem Rev. 2024; 124(20):11523-11543.

PMID: 39207057 PMC: 11503617. DOI: 10.1021/acs.chemrev.4c00306.

Mono-allelic KCNB2 variants lead to a neurodevelopmental syndrome caused by altered channel inactivation.

Bhat S, Rousseau J, Michaud C, Lourenco C, Stoler J, Louie R Am J Hum Genet. 2024; 111(4):761-777.

PMID: 38503299 PMC: 11023922. DOI: 10.1016/j.ajhg.2024.02.014.

Bioelectronic Medicine: a multidisciplinary roadmap from biophysics to precision therapies.

Gonzalez-Gonzalez M, Conde S, Latorre R, Thebault S, Pratelli M, Spitzer N Front Integr Neurosci. 2024; 18:1321872.

PMID: 38440417 PMC: 10911101. DOI: 10.3389/fnint.2024.1321872.

References

Piper D, Varghese A, Sanguinetti M, Tristani-Firouzi M . Gating currents associated with intramembrane charge displacement in HERG potassium channels. Proc Natl Acad Sci U S A. 2003; 100(18):10534-9. PMC: 193596. DOI: 10.1073/pnas.1832721100. View

Lu Z, Klem A, Ramu Y . Coupling between voltage sensors and activation gate in voltage-gated K+ channels. J Gen Physiol. 2002; 120(5):663-76. PMC: 2229552. DOI: 10.1085/jgp.20028696. View

Tang C, Bezanilla F, Papazian D . Extracellular Mg(2+) modulates slow gating transitions and the opening of Drosophila ether-à-Go-Go potassium channels. J Gen Physiol. 2000; 115(3):319-38. PMC: 2217207. DOI: 10.1085/jgp.115.3.319. View

Wang W, MacKinnon R . Cryo-EM Structure of the Open Human Ether-à-go-go-Related K Channel hERG. Cell. 2017; 169(3):422-430.e10. PMC: 5484391. DOI: 10.1016/j.cell.2017.03.048. View

Faure E, Starek G, McGuire H, Berneche S, Blunck R . A limited 4 Å radial displacement of the S4-S5 linker is sufficient for internal gate closing in Kv channels. J Biol Chem. 2012; 287(47):40091-8. PMC: 3501078. DOI: 10.1074/jbc.M112.415497. View

Hackos D, Swartz K . A localized interaction surface for voltage-sensing domains on the pore domain of a K+ channel. Neuron. 2000; 25(2):411-23. DOI: 10.1016/s0896-6273(00)80904-6. View

Batulan Z, Haddad G, Blunck R . An intersubunit interaction between S4-S5 linker and S6 is responsible for the slow off-gating component in Shaker K+ channels. J Biol Chem. 2010; 285(18):14005-19. PMC: 2859562. DOI: 10.1074/jbc.M109.097717. View

Stefani E, Toro L, Perozo E, Bezanilla F . Gating of Shaker K+ channels: I. Ionic and gating currents. Biophys J. 1994; 66(4):996-1010. PMC: 1275807. DOI: 10.1016/S0006-3495(94)80881-1. View

Lee H, Guo J, Lemke E, Dimla R, Schultz P . Genetic incorporation of a small, environmentally sensitive, fluorescent probe into proteins in Saccharomyces cerevisiae. J Am Chem Soc. 2009; 131(36):12921-3. PMC: 2873857. DOI: 10.1021/ja904896s. View

10.

Long S, Campbell E, MacKinnon R . Voltage sensor of Kv1.2: structural basis of electromechanical coupling. Science. 2005; 309(5736):903-8. DOI: 10.1126/science.1116270. View

11.

Wulff H, Castle N, Pardo L . Voltage-gated potassium channels as therapeutic targets. Nat Rev Drug Discov. 2009; 8(12):982-1001. PMC: 2790170. DOI: 10.1038/nrd2983. View

12.

Zhao J, Blunck R . The isolated voltage sensing domain of the Shaker potassium channel forms a voltage-gated cation channel. Elife. 2016; 5. PMC: 5092046. DOI: 10.7554/eLife.18130. View

13.

Berneche S, Roux B . A gate in the selectivity filter of potassium channels. Structure. 2005; 13(4):591-600. DOI: 10.1016/j.str.2004.12.019. View

14.

Goodchild S, Fedida D . Gating charge movement precedes ionic current activation in hERG channels. Channels (Austin). 2013; 8(1):84-9. PMC: 4048346. DOI: 10.4161/chan.26775. View

15.

Chatterjee A, Guo J, Lee H, Schultz P . A genetically encoded fluorescent probe in mammalian cells. J Am Chem Soc. 2013; 135(34):12540-3. PMC: 3783214. DOI: 10.1021/ja4059553. View

16.

Barghaan J, Bahring R . Dynamic coupling of voltage sensor and gate involved in closed-state inactivation of kv4.2 channels. J Gen Physiol. 2009; 133(2):205-24. PMC: 2638201. DOI: 10.1085/jgp.200810073. View

17.

Long S, Tao X, Campbell E, MacKinnon R . Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature. 2007; 450(7168):376-82. DOI: 10.1038/nature06265. View

18.

Bezanilla F . How membrane proteins sense voltage. Nat Rev Mol Cell Biol. 2008; 9(4):323-32. DOI: 10.1038/nrm2376. View

19.

Labro A, Raes A, Grottesi A, Van Hoorick D, Sansom M, Snyders D . Kv channel gating requires a compatible S4-S5 linker and bottom part of S6, constrained by non-interacting residues. J Gen Physiol. 2008; 132(6):667-80. PMC: 2585865. DOI: 10.1085/jgp.200810048. View

20.

Bezanilla F, Perozo E, Stefani E . Gating of Shaker K+ channels: II. The components of gating currents and a model of channel activation. Biophys J. 1994; 66(4):1011-21. PMC: 1275808. DOI: 10.1016/S0006-3495(94)80882-3. View