Role of the C-terminal domain in the structure and function of tetrameric sodium channels

Claire Bagnéris; Paul G. Decaen; Benjamin A. Hall; Claire E. Naylor; David E. Clapham; Christopher W M Kay; B. A. Wallace

doi:10.1038/ncomms3465

Role of the C-terminal domain in the structure and function of tetrameric sodium channels

Claire Bagnéris, Paul G. Decaen, Benjamin A. Hall, Claire E. Naylor, David E. Clapham, Christopher W M Kay, B. A. Wallace^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

Abstract

Voltage-gated sodium channels have essential roles in electrical signalling. Prokaryotic sodium channels are tetramers consisting of transmembrane (TM) voltage-sensing and pore domains, and a cytoplasmic carboxy-terminal domain. Previous crystal structures of bacterial sodium channels revealed the nature of their TM domains but not their C-terminal domains (CTDs). Here, using electron paramagnetic resonance (EPR) spectroscopy combined with molecular dynamics, we show that the CTD of the NavMs channel from Magnetococcus marinus includes a flexible region linking the TM domains to a four-helix coiled-coil bundle. A 2.9 Å resolution crystal structure of the NavMs pore indicates the position of the CTD, which is consistent with the EPR-derived structure. Functional analyses demonstrate that the coiled-coil domain couples inactivation with channel opening, and is enabled by negatively charged residues in the linker region. A mechanism for gating is proposed based on the structure, whereby splaying of the bottom of the pore is possible without requiring unravelling of the coiled-coil.

Original language	English (US)
Article number	2465
Journal	Nature communications
Volume	4
DOIs	https://doi.org/10.1038/ncomms3465
State	Published - 2013

ASJC Scopus subject areas

General
Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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@article{41a89b5ac25840959344f168c486e468,

title = "Role of the C-terminal domain in the structure and function of tetrameric sodium channels",

abstract = "Voltage-gated sodium channels have essential roles in electrical signalling. Prokaryotic sodium channels are tetramers consisting of transmembrane (TM) voltage-sensing and pore domains, and a cytoplasmic carboxy-terminal domain. Previous crystal structures of bacterial sodium channels revealed the nature of their TM domains but not their C-terminal domains (CTDs). Here, using electron paramagnetic resonance (EPR) spectroscopy combined with molecular dynamics, we show that the CTD of the NavMs channel from Magnetococcus marinus includes a flexible region linking the TM domains to a four-helix coiled-coil bundle. A 2.9 {\AA} resolution crystal structure of the NavMs pore indicates the position of the CTD, which is consistent with the EPR-derived structure. Functional analyses demonstrate that the coiled-coil domain couples inactivation with channel opening, and is enabled by negatively charged residues in the linker region. A mechanism for gating is proposed based on the structure, whereby splaying of the bottom of the pore is possible without requiring unravelling of the coiled-coil.",

author = "Claire Bagn{\'e}ris and Decaen, {Paul G.} and Hall, {Benjamin A.} and Naylor, {Claire E.} and Clapham, {David E.} and Kay, {Christopher W M} and Wallace, {B. A.}",

note = "Funding Information: This work was supported by grants from the UK Biotechnology and Biological Science Research Council (BBSRC) to B.A.W. and a Basic Technology {\textquoteleft}Molecular Spintronics{\textquoteright} grant from the UK Engineering and Physical Sciences (EPSRC) to CWMK. We thank Dr Emily McCusker for designing NavMs-pore + CTD construct. We also thank the Membrane Protein Laboratory (Diamond Light Source, UK) for their expertise, support and helpful discussions, and are grateful for the help of Dr Ambrose Cole (Birkbeck College) and the beamline scientists at the Diamond Light Source, UK (beamlines IO4-1, Pierpaolo Romano, IO2, James Sandy) and Soleil, France (beamline Proxima 1, Andrew Thompson).",

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journal = "Nature Communications",

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AU - Bagnéris, Claire

AU - Decaen, Paul G.

AU - Hall, Benjamin A.

AU - Naylor, Claire E.

AU - Clapham, David E.

AU - Kay, Christopher W M

AU - Wallace, B. A.

N1 - Funding Information: This work was supported by grants from the UK Biotechnology and Biological Science Research Council (BBSRC) to B.A.W. and a Basic Technology ‘Molecular Spintronics’ grant from the UK Engineering and Physical Sciences (EPSRC) to CWMK. We thank Dr Emily McCusker for designing NavMs-pore + CTD construct. We also thank the Membrane Protein Laboratory (Diamond Light Source, UK) for their expertise, support and helpful discussions, and are grateful for the help of Dr Ambrose Cole (Birkbeck College) and the beamline scientists at the Diamond Light Source, UK (beamlines IO4-1, Pierpaolo Romano, IO2, James Sandy) and Soleil, France (beamline Proxima 1, Andrew Thompson).

PY - 2013

Y1 - 2013

N2 - Voltage-gated sodium channels have essential roles in electrical signalling. Prokaryotic sodium channels are tetramers consisting of transmembrane (TM) voltage-sensing and pore domains, and a cytoplasmic carboxy-terminal domain. Previous crystal structures of bacterial sodium channels revealed the nature of their TM domains but not their C-terminal domains (CTDs). Here, using electron paramagnetic resonance (EPR) spectroscopy combined with molecular dynamics, we show that the CTD of the NavMs channel from Magnetococcus marinus includes a flexible region linking the TM domains to a four-helix coiled-coil bundle. A 2.9 Å resolution crystal structure of the NavMs pore indicates the position of the CTD, which is consistent with the EPR-derived structure. Functional analyses demonstrate that the coiled-coil domain couples inactivation with channel opening, and is enabled by negatively charged residues in the linker region. A mechanism for gating is proposed based on the structure, whereby splaying of the bottom of the pore is possible without requiring unravelling of the coiled-coil.

AB - Voltage-gated sodium channels have essential roles in electrical signalling. Prokaryotic sodium channels are tetramers consisting of transmembrane (TM) voltage-sensing and pore domains, and a cytoplasmic carboxy-terminal domain. Previous crystal structures of bacterial sodium channels revealed the nature of their TM domains but not their C-terminal domains (CTDs). Here, using electron paramagnetic resonance (EPR) spectroscopy combined with molecular dynamics, we show that the CTD of the NavMs channel from Magnetococcus marinus includes a flexible region linking the TM domains to a four-helix coiled-coil bundle. A 2.9 Å resolution crystal structure of the NavMs pore indicates the position of the CTD, which is consistent with the EPR-derived structure. Functional analyses demonstrate that the coiled-coil domain couples inactivation with channel opening, and is enabled by negatively charged residues in the linker region. A mechanism for gating is proposed based on the structure, whereby splaying of the bottom of the pore is possible without requiring unravelling of the coiled-coil.

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Role of the C-terminal domain in the structure and function of tetrameric sodium channels

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