View source for 2kbi


==Solution NMR structure of the C-terminal EF-hand domain of human cardiac sodium channel NaV1.5==
<StructureSection load='2kbi' size='340' side='right'caption='[[2kbi]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2kbi]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2KBI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2KBI FirstGlance]. <br>
</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SCN5A ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2kbi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2kbi OCA], [https://pdbe.org/2kbi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2kbi RCSB], [https://www.ebi.ac.uk/pdbsum/2kbi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2kbi ProSAT]</span></td></tr>
</table>
== Disease ==
[[https://www.uniprot.org/uniprot/SCN5A_HUMAN SCN5A_HUMAN]] Defects in SCN5A are a cause of progressive familial heart block type 1A (PFHB1A) [MIM:[https://omim.org/entry/113900 113900]]; also known as Lenegre-Lev disease or progressive cardiac conduction defect (PCCD). PFHB1A is an autosomal dominant cardiac bundle branch disorder that may progress to complete heart block. PFHB1A is characterized by progressive alteration of cardiac conduction through the His-Purkinje system with right or left bundle branch block and widening of QRS complexes, leading to complete atrioventricular block and causing syncope and sudden death.<ref>PMID:10471492</ref> <ref>PMID:11234013</ref> <ref>PMID:11804990</ref> <ref>PMID:12574143</ref> <ref>PMID:12569159</ref> <ref>PMID:19251209</ref>   Defects in SCN5A are the cause of long QT syndrome type 3 (LQT3) [MIM:[https://omim.org/entry/603830 603830]]. Long QT syndromes are heart disorders characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress. LQT3 inheritance is an autosomal dominant.<ref>PMID:10471492</ref> <ref>PMID:12454206</ref> <ref>PMID:7889574</ref> <ref>PMID:8541846</ref> <ref>PMID:7651517</ref> <ref>PMID:9686753</ref> <ref>PMID:9506831</ref> <ref>PMID:10627139</ref> [:]<ref>PMID:10508990</ref> <ref>PMID:10377081</ref> <ref>PMID:10590249</ref> <ref>PMID:10973849</ref> <ref>PMID:10911008</ref> <ref>PMID:11304498</ref> <ref>PMID:11410597</ref> <ref>PMID:11710892</ref> <ref>PMID:11889015</ref> <ref>PMID:11997281</ref> <ref>PMID:12209021</ref> <ref>PMID:12673799</ref> <ref>PMID:15840476</ref> <ref>PMID:16922724</ref> <ref>PMID:18708744</ref> <ref>PMID:18060054</ref> <ref>PMID:18929331</ref> <ref>PMID:18848812</ref> <ref>PMID:18451998</ref> <ref>PMID:21109022</ref>   Defects in SCN5A are the cause of Brugada syndrome type 1 (BRGDA1) [MIM:[https://omim.org/entry/601144 601144]]. An autosomal dominant tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs (called ventricular fibrillation), the individual will faint and may die in a few minutes if the heart is not reset.<ref>PMID:10471492</ref> <ref>PMID:19251209</ref> <ref>PMID:11410597</ref> <ref>PMID:9521325</ref> <ref>PMID:10690282</ref> <ref>PMID:10532948</ref> <ref>PMID:10618304</ref> <ref>PMID:12106943</ref> <ref>PMID:11901046</ref> <ref>PMID:11823453</ref> <ref>PMID:12051963</ref> <ref>PMID:15023552</ref> <ref>PMID:15338453</ref> <ref>PMID:15579534</ref> <ref>PMID:16266370</ref> <ref>PMID:15851320</ref> <ref>PMID:16325048</ref> <ref>PMID:16616735</ref> <ref>PMID:17075016</ref> <ref>PMID:17081365</ref> <ref>PMID:17198989</ref> <ref>PMID:18341814</ref> <ref>PMID:18616619</ref> <ref>PMID:18456723</ref> <ref>PMID:18252757</ref> <ref>PMID:19272188</ref>   Defects in SCN5A are the cause of sick sinus syndrome type 1 (SSS1) [MIM:[https://omim.org/entry/608567 608567]]. The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors, in which case it is considered to be a congenital disorder.<ref>PMID:10471492</ref> <ref>PMID:11748104</ref> <ref>PMID:14523039</ref> <ref>PMID:22795782</ref>   Defects in SCN5A are the cause of familial paroxysmal ventricular fibrillation type 1 (VF1) [MIM:[https://omim.org/entry/603829 603829]]. A cardiac arrhythmia marked by fibrillary contractions of the ventricular muscle due to rapid repetitive excitation of myocardial fibers without coordinated contraction of the ventricle and by absence of atrial activity.<ref>PMID:10471492</ref> <ref>PMID:10940383</ref>   Defects in SCN5A may be a cause of sudden infant death syndrome (SIDS) [MIM:[https://omim.org/entry/272120 272120]]. SIDS is the sudden death of an infant younger than 1 year that remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of clinical history. Pathophysiologic mechanisms for SIDS may include respiratory dysfunction, cardiac dysrhythmias, cardiorespiratory instability, and inborn errors of metabolism, but definitive pathogenic mechanisms precipitating an infant sudden death remain elusive. Long QT syndromes-associated mutations can be responsible for some of SIDS cases.<ref>PMID:10471492</ref> <ref>PMID:18596570</ref> <ref>PMID:19302788</ref>   Defects in SCN5A may be a cause of familial atrial standstill (FAS) [MIM:[https://omim.org/entry/108770 108770]]. Atrial standstill is an extremely rare arrhythmia, characterized by the absence of electrical and mechanical activity in the atria. Electrocardiographically, it is characterized by bradycardia, the absence of P waves, and a junctional narrow complex escape rhythm.<ref>PMID:10471492</ref> <ref>PMID:12522116</ref>   Defects in SCN5A are the cause of cardiomyopathy dilated type 1E (CMD1E) [MIM:[https://omim.org/entry/601154 601154]]; also known as dilated cardiomyopathy with conduction disorder and arrhythmia or dilated cardiomyopathy with conduction defect 2. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.<ref>PMID:10471492</ref> <ref>PMID:15466643</ref>   Defects in SCN5A are the cause of familial atrial fibrillation type 10 (ATFB10) [MIM:[https://omim.org/entry/614022 614022]]. ATFB10 is a familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure.<ref>PMID:10471492</ref> <ref>PMID:18378609</ref> <ref>PMID:18088563</ref>  
== Function ==
[[https://www.uniprot.org/uniprot/SCN5A_HUMAN SCN5A_HUMAN]] This protein 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. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential. Channel inactivation is regulated by intracellular calcium levels.<ref>PMID:19074138</ref>  
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/kb/2kbi_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2kbi ConSurf].
<div style="clear:both"></div>
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== Publication Abstract from PubMed ==
The voltage-gated sodium channel NaV1.5 is responsible for the initial upstroke of the action potential in cardiac tissue. Levels of intracellular calcium modulate inactivation gating of NaV1.5, in part through a C-terminal EF-hand calcium binding domain. The significance of this structure is underscored by the fact that mutations within this domain are associated with specific cardiac arrhythmia syndromes. In an effort to elucidate the molecular basis for calcium regulation of channel function, we have determined the solution structure of the C-terminal EF-hand domain using multidimensional heteronuclear NMR. The structure confirms the existence of the four-helix bundle common to EF-hand domain proteins. However, the location of this domain is shifted with respect to that predicted on the basis of a consensus 12-residue EF-hand calcium binding loop in the sequence. This finding is consistent with the weak calcium affinity reported for the isolated EF-hand domain; high affinity binding is observed only in a construct with an additional 60 residues C-terminal to the EF-hand domain, including the IQ motif that is central to the calcium regulatory apparatus. The binding of an IQ motif peptide to the EF-hand domain was characterized by isothermal titration calorimetry and nuclear magnetic resonance spectroscopy. The peptide binds between helices I and IV in the EF-hand domain, similar to the binding of target peptides to other EF-hand calcium-binding proteins. These results suggest a molecular basis for the coupling of the intrinsic (EF-hand domain) and extrinsic (calmodulin) components of the calcium-sensing apparatus of NaV1.5.

Solution NMR structure of the C-terminal EF-hand domain of human cardiac sodium channel NaV1.5.,Chagot B, Potet F, Balser JR, Chazin WJ J Biol Chem. 2009 Mar 6;284(10):6436-45. Epub 2008 Dec 11. PMID:19074138<ref>PMID:19074138</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 2kbi" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ion channels 3D structures|Ion channels 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Balser, J R]]
[[Category: Chagot, B]]
[[Category: Chazin, W J]]
[[Category: Potet, F]]
[[Category: Brugada syndrome]]
[[Category: Cardiomyopathy]]
[[Category: Disease mutation]]
[[Category: Ef-hand]]
[[Category: Glycoprotein]]
[[Category: Ion transport]]
[[Category: Ionic channel]]
[[Category: Long qt syndrome]]
[[Category: Membrane]]
[[Category: Metal binding protein]]
[[Category: Phosphoprotein]]
[[Category: Polymorphism]]
[[Category: Protein]]
[[Category: Sodium]]
[[Category: Sodium channel]]
[[Category: Sodium transport]]
[[Category: Transmembrane]]
[[Category: Transport]]
[[Category: Ubl conjugation]]
[[Category: Voltage-gated channel]]