2KAV

Solution structure of the human Voltage-gated Sodium Channel, brain isoform (Nav1.2)

Summary for 2KAV

• Entry DOI: 10.2210/pdb2kav/pdb
• Related: 1byy 1qg9
• NMR Information: BMRB: 16032
• Descriptor: Sodium channel protein type 2 subunit alpha (1 entity in total)
• Functional Keywords: voltage-gated sodium channel, alternative splicing, disease mutation, epilepsy, glycoprotein, ion transport, ionic channel, membrane, polymorphism, sodium, sodium channel, sodium transport, transmembrane, transport, ubl conjugation, voltage-gated channel, transport protein, transport protein regulator
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Multi-pass membrane protein: Q99250
• Total number of polymer chains: 1
• Total formula weight: 14591.39

Authors

Miloushev, V.Z.,Levine, J.A.,Arbing, M.A.,Hunt, J.F.,Pitt, G.S.,Palmer, A.G. (deposition date: 2008-11-15, release date: 2009-01-06, Last modification date: 2024-05-22)

Primary citation

Miloushev, V.Z.,Levine, J.A.,Arbing, M.A.,Hunt, J.F.,Pitt, G.S.,Palmer, A.G.
Solution structure of the NaV1.2 C-terminal EF-hand domain.
J.Biol.Chem., 284:6446-6454, 2009

PubMed Abstract: Voltage-gated sodium channels initiate the rapid upstroke of action potentials in many excitable tissues. Mutations within intracellular C-terminal sequences of specific channels underlie a diverse set of channelopathies, including cardiac arrhythmias and epilepsy syndromes. The three-dimensional structure of the C-terminal residues 1777-1882 of the human NaV1.2 voltage-gated sodium channel has been determined in solution by NMR spectroscopy at pH 7.4 and 290.5 K. The ordered structure extends from residues Leu-1790 to Glu-1868 and is composed of four alpha-helices separated by two short anti-parallel beta-strands; a less well defined helical region extends from residue Ser-1869 to Arg-1882, and a disordered N-terminal region encompasses residues 1777-1789. Although the structure has the overall architecture of a paired EF-hand domain, the NaV1.2 C-terminal domain does not bind Ca2+ through the canonical EF-hand loops, as evidenced by monitoring 1H,15N chemical shifts during aCa2+ titration. Backbone chemical shift resonance assignments and Ca2+ titration also were performed for the NaV1.5 (1773-1878) isoform, demonstrating similar secondary structure architecture and the absence of Ca2+ binding by the EF-hand loops. Clinically significant mutations identified in the C-terminal region of NaV1 sodium channels cluster in the helix I-IV interface and the helix II-III interhelical segment or in helices III and IV of the NaV1.2 (1777-1882) structure.

PubMed: 19129176
DOI: 10.1074/jbc.M807401200

Experimental method

SOLUTION NMR