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

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