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Title: Crystal Structure of the Ternary Complex of a NaV C-Terminal Domain, a Fibroblast Growth Factor Homologous Factor, and Calmodulin

Abstract

Voltage-gated Na{sup +} (Na{sub V}) channels initiate neuronal action potentials. Na{sub V} channels are composed of a transmembrane domain responsible for voltage-dependent Na{sup +} conduction and a cytosolic C-terminal domain (CTD) that regulates channel function through interactions with many auxiliary proteins, including fibroblast growth factor homologous factors (FHFs) and calmodulin (CaM). Most ion channel structural studies have focused on mechanisms of permeation and voltage-dependent gating but less is known about how intracellular domains modulate channel function. Here we report the crystal structure of the ternary complex of a human NaV CTD, an FHF, and Ca{sup 2+}-free CaM at 2.2 {angstrom}. Combined with functional experiments based on structural insights, we present a platform for understanding the roles of these auxiliary proteins in NaV channel regulation and the molecular basis of mutations that lead to neuronal and cardiac diseases. Furthermore, we identify a critical interaction that contributes to the specificity of individual NaV CTD isoforms for distinctive FHFs.

Authors:
; ; ; ;  [1]
  1. (Duke)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
AHAOTHERUNIVERSITYNIH
OSTI Identifier:
1048567
Resource Type:
Journal Article
Journal Name:
Structure
Additional Journal Information:
Journal Volume: 20; Journal Issue: (7) ; 07, 2012
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CALMODULIN; CRYSTAL STRUCTURE; DISEASES; FIBROBLASTS; FUNCTIONALS; GROWTH FACTORS; MUTATIONS; PROTEINS; REGULATIONS; SPECIFICITY

Citation Formats

Wang, Chaojian, Chung, Ben C., Yan, Haidun, Lee, Seok-Yong, and Pitt, Geoffrey S. Crystal Structure of the Ternary Complex of a NaV C-Terminal Domain, a Fibroblast Growth Factor Homologous Factor, and Calmodulin. United States: N. p., 2012. Web. doi:10.1016/j.str.2012.05.001.
Wang, Chaojian, Chung, Ben C., Yan, Haidun, Lee, Seok-Yong, & Pitt, Geoffrey S. Crystal Structure of the Ternary Complex of a NaV C-Terminal Domain, a Fibroblast Growth Factor Homologous Factor, and Calmodulin. United States. doi:10.1016/j.str.2012.05.001.
Wang, Chaojian, Chung, Ben C., Yan, Haidun, Lee, Seok-Yong, and Pitt, Geoffrey S. Tue . "Crystal Structure of the Ternary Complex of a NaV C-Terminal Domain, a Fibroblast Growth Factor Homologous Factor, and Calmodulin". United States. doi:10.1016/j.str.2012.05.001.
@article{osti_1048567,
title = {Crystal Structure of the Ternary Complex of a NaV C-Terminal Domain, a Fibroblast Growth Factor Homologous Factor, and Calmodulin},
author = {Wang, Chaojian and Chung, Ben C. and Yan, Haidun and Lee, Seok-Yong and Pitt, Geoffrey S.},
abstractNote = {Voltage-gated Na{sup +} (Na{sub V}) channels initiate neuronal action potentials. Na{sub V} channels are composed of a transmembrane domain responsible for voltage-dependent Na{sup +} conduction and a cytosolic C-terminal domain (CTD) that regulates channel function through interactions with many auxiliary proteins, including fibroblast growth factor homologous factors (FHFs) and calmodulin (CaM). Most ion channel structural studies have focused on mechanisms of permeation and voltage-dependent gating but less is known about how intracellular domains modulate channel function. Here we report the crystal structure of the ternary complex of a human NaV CTD, an FHF, and Ca{sup 2+}-free CaM at 2.2 {angstrom}. Combined with functional experiments based on structural insights, we present a platform for understanding the roles of these auxiliary proteins in NaV channel regulation and the molecular basis of mutations that lead to neuronal and cardiac diseases. Furthermore, we identify a critical interaction that contributes to the specificity of individual NaV CTD isoforms for distinctive FHFs.},
doi = {10.1016/j.str.2012.05.001},
journal = {Structure},
number = (7) ; 07, 2012,
volume = 20,
place = {United States},
year = {2012},
month = {11}
}