Structural and energetic determinants of apo calmodulin binding to the IQ motif of the Na(V)1.2 voltage-dependent sodium channel

Michael D Feldkamp; Liping Yu; Madeline A Shea

doi:10.1016/j.str.2011.02.009

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Structural and energetic determinants of apo calmodulin binding to the IQ motif of the Na(V)1.2 voltage-dependent sodium channel

Journal article

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Structural and energetic determinants of apo calmodulin binding to the IQ motif of the Na(V)1.2 voltage-dependent sodium channel

Michael D Feldkamp, Liping Yu and Madeline A Shea

Structure (London), Vol.19(5), pp.733-747

05/11/2011

DOI: 10.1016/j.str.2011.02.009

PMCID: PMC3094505

PMID: 21439835

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Abstract

The neuronal voltage-dependent sodium channel (Na(v)1.2), essential for generation and propagation of action potentials, is regulated by calmodulin (CaM) binding to the IQ motif in its α subunit. A peptide (Na(v)1.2(IQp), KRKQEEVSAIVIQRAYRRYLLKQKVKK) representing the IQ motif had higher affinity for apo CaM than (Ca(2+))(4)-CaM. Association was mediated solely by the C-domain of CaM. A solution structure (2KXW.pdb) of apo (13)C,(15)N-CaM C-domain bound to Na(v)1.2(IQp) was determined with NMR. The region of Na(v)1.2(IQp) bound to CaM was helical; R1902, an Na(v)1.2 residue implicated in familial autism, did not contact CaM. The apo C-domain of CaM in this complex shares features of the same domain bound to myosin V IQ motifs (2IX7) and bound to an SK channel peptide (1G4Y) that does not contain an IQ motif. Thermodynamic and structural studies of CaM-Na(v)1.2(IQp) interactions show that apo and (Ca(2+))(4)-CaM adopt distinct conformations that both permit tight association with Na(v)1.2(IQp) during gating.

Apoproteins - chemistry

Calmodulin - genetics

Myosin Type V - chemistry

Calcium - metabolism

Escherichia coli

Humans

Molecular Sequence Data

Thermodynamics

Nerve Tissue Proteins - chemistry

Peptides - chemical synthesis

Peptides - metabolism

Cloning, Molecular

Sodium Channels - metabolism

Nuclear Magnetic Resonance, Biomolecular

Calmodulin - chemistry

Apoproteins - metabolism

Protein Structure, Tertiary

Recombinant Proteins - metabolism

Amino Acid Sequence

Calmodulin - metabolism

Myosin Type V - metabolism

Protein Structure, Secondary

Models, Molecular

Recombinant Proteins - chemistry

Recombinant Proteins - genetics

Nerve Tissue Proteins - genetics

Action Potentials - physiology

Nerve Tissue Proteins - metabolism

Sodium Channels - chemistry

Apoproteins - genetics

Protein Binding

Sodium Channels - genetics

NAV1.2 Voltage-Gated Sodium Channel

Details

Title: Subtitle: Structural and energetic determinants of apo calmodulin binding to the IQ motif of the Na(V)1.2 voltage-dependent sodium channel
Creators: Michael D Feldkamp - Department of Biochemistry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242-1109, USA
Liping Yu
Madeline A Shea
Resource Type: Journal article
Publication Details: Structure (London), Vol.19(5), pp.733-747
Publisher: United States
DOI: 10.1016/j.str.2011.02.009
PMID: 21439835
PMCID: PMC3094505
ISSN: 0969-2126
eISSN: 1878-4186
Grant note: R01 GM057001 / NIGMS NIH HHS R01 GM 57001 / NIGMS NIH HHS R01 GM057001-08 / NIGMS NIH HHS
Language: English
Date published: 05/11/2011
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology; Medicine Administration
Record Identifier: 9984025399302771

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