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

Nat Commun. 2013;4:2465. doi: 10.1038/ncomms3465.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alphaproteobacteria / chemistry*
  • Alphaproteobacteria / metabolism
  • Amino Acid Sequence
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / genetics
  • Crystallography, X-Ray
  • Electron Spin Resonance Spectroscopy
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Ion Channel Gating
  • Molecular Dynamics Simulation*
  • Molecular Sequence Data
  • Protein Multimerization
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Static Electricity
  • Voltage-Gated Sodium Channels / chemistry*
  • Voltage-Gated Sodium Channels / genetics

Substances

  • Bacterial Proteins
  • Recombinant Proteins
  • Voltage-Gated Sodium Channels