2kav
Solution structure of the human Voltage-gated Sodium Channel, brain isoform (Nav1.2)
Structural highlights
DiseaseSCN2A_HUMAN Defects in SCN2A are the cause of seizures, benign familial infantile type 3 (BFIS3) [MIM:607745. An autosomal dominant disorder in which afebrile seizures occur in clusters during the first year of life, without neurologic sequelae.[1] [2] [3] [4] Defects in SCN2A are the cause of epileptic encephalopathy early infantile type 11 (EIEE11) [MIM:613721. EIEE11 is an autosomal dominant seizure disorder characterized by infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities.[5] [6] FunctionSCN2A_HUMAN Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedVoltage-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. Solution structure of the NaV1.2 C-terminal EF-hand domain.,Miloushev VZ, Levine JA, Arbing MA, Hunt JF, Pitt GS, Palmer AG 3rd J Biol Chem. 2009 Mar 6;284(10):6446-54. Epub 2009 Jan 7. PMID:19129176[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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