The complete structure of an activated open sodium channel

Altin Sula,Leo C. T. Ng,Claire E. Naylor,Jennifer Booker,B. A. Wallace,Paul G. DeCaen

doi:10.1038/ncomms14205

Abstract

Voltage-gated sodium channels (Navs) play essential roles in excitable tissues, with their activation and opening resulting in the initial phase of the action potential. The cycling of Navs through open, closed and inactivated states, and their closely choreographed relationships with the activities of other ion channels lead to exquisite control of intracellular ion concentrations in both prokaryotes and eukaryotes. Here we present the 2.45 Å resolution crystal structure of the complete NavMs prokaryotic sodium channel in a fully open conformation. A canonical activated conformation of the voltage sensor S4 helix, an open selectivity filter leading to an open activation gate at the intracellular membrane surface and the intracellular C-terminal domain are visible in the structure. It includes a heretofore unseen interaction motif between W77 of S3, the S4–S5 interdomain linker, and the C-terminus, which is associated with regulation of opening and closing of the intracellular gate.

Highlights

Voltage-gated sodium channels (Navs) play essential roles in excitable tissues, with their activation and opening resulting in the initial phase of the action potential
Prokaryotic sodium channels, in contrast, are true tetrameric structures, composed of four identical subunits, each one equivalent to a single eukaryotic region. Both eukaryotic and prokaryotic Navs consist of voltage sensor (VS) and pore domains, which are responsible for regulation and ion-translocation functions, respectively, and C-terminal domains (CTDs), which appear in both cases to have regulatory functions, albeit of quite different natures and structures
Whilst no structures have yet been produced for eukaryotic sodium channels, a number of crystal structures of prokaryotic sodium channels in different conformations with different regions of their structures visible[1,2,3,5,6,7,8,9] have provided insights[10] into functionally-related structural features of this important family of ion channels

Summary

Introduction

Voltage-gated sodium channels (Navs) play essential roles in excitable tissues, with their activation and opening resulting in the initial phase of the action potential. Prokaryotic sodium channels, in contrast, are true tetrameric structures, composed of four identical subunits, each one equivalent to a single eukaryotic region Both eukaryotic and prokaryotic Navs consist of voltage sensor (VS) and pore domains, which are responsible for regulation and ion-translocation functions, respectively, and C-terminal domains (CTDs), which appear in both cases to have regulatory functions, albeit of quite different natures and structures. The structure displays an activated VS domain conformation, three sodium ions present in its open selectivity filter, and an open intracellular pore gate formed from the S6 transmembrane helices leading into a regulatory CTD It has revealed the nature of an interaction domain that forms the basis for understanding the opening and closing of the intracellular gate, and indicated a set of residues essential for enabling the open conformation, including signature residues that are conserved across prokaryotic and eukaryotic sodium channels. The present study combining structural biology and electrophysiology has enabled identification of the molecular basis of gating of this sodium channel

Methods

Results

Conclusion