Solution NMR structure of Apo-calmodulin in complex with the IQ motif of human cardiac sodium channel NaV1.5.

Chagot B, Chazin WJ
J Mol Biol. 2011 406 (1): 106-19

PMID: 21167176 · PMCID: PMC3030672 · DOI:10.1016/j.jmb.2010.11.046

The function of the human voltage-gated sodium channel Na(V)1.5 is regulated in part by intracellular calcium signals. The ubiquitous calcium sensor protein calmodulin (CaM) is an important part of the complex calcium-sensing apparatus in Na(V)1.5. CaM interacts with an IQ (isoleucine-glutamine) motif in the large intracellular C-terminal domain of the channel. Using co-expression and co-purification, we have been able to isolate a CaM-IQ motif complex and to determine its high-resolution structure in absence of calcium using multi-dimensional solution NMR. Under these conditions, the Na(V)1.5 IQ motif interacts with the C-terminal domain (C-lobe) of CaM, with the N-terminal domain remaining free in solution. The structure reveals that the C-lobe adopts a semi-open conformation with the IQ motif bound in a narrow hydrophobic groove. Sequence similarities between voltage-gated sodium channels and voltage-gated calcium channels suggest that the structure of the CaM-Na(V)1.5 IQ motif complex can serve as a general model for the interaction between CaM and ion channel IQ motifs under low-calcium conditions. The structure also provides insight into the biochemical basis for disease-associated mutations that map to the IQ motif in Na(V)1.5.

Copyright © 2010 Elsevier Ltd. All rights reserved.

MeSH Terms (16)

Amino Acid Sequence Calcium Calcium Channels Calmodulin Humans Molecular Sequence Data Muscle Proteins Mutation NAV1.5 Voltage-Gated Sodium Channel Nuclear Magnetic Resonance, Biomolecular Protein Conformation Protein Interaction Domains and Motifs Protein Structure, Secondary Sequence Alignment Sequence Homology, Amino Acid Sodium Channels

Connections (1)

This publication is referenced by other Labnodes entities: