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==Solution NMR structure of the C-terminal EF-hand domain of human cardiac sodium channel NaV1.5==
==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=''>
<StructureSection load='2kbi' size='340' side='right'caption='[[2kbi]]' scene=''>
== Structural highlights ==
== 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>
<table><tr><td colspan='2'>[[2kbi]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. 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>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</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>
<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>
</table>
== Disease ==
== 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>
[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 ==
== 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>
[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 ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Balser, J R]]
[[Category: Balser JR]]
[[Category: Chagot, B]]
[[Category: Chagot B]]
[[Category: Chazin, W J]]
[[Category: Chazin WJ]]
[[Category: Potet, F]]
[[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]]

Latest revision as of 12:37, 22 May 2024

Solution NMR structure of the C-terminal EF-hand domain of human cardiac sodium channel NaV1.5Solution NMR structure of the C-terminal EF-hand domain of human cardiac sodium channel NaV1.5

Structural highlights

2kbi is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

SCN5A_HUMAN Defects in SCN5A are a cause of progressive familial heart block type 1A (PFHB1A) [MIM: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.[1] [2] [3] [4] [5] [6] Defects in SCN5A are the cause of long QT syndrome type 3 (LQT3) [MIM: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.[7] [8] [9] [10] [11] [12] [13] [14] [:][15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] Defects in SCN5A are the cause of Brugada syndrome type 1 (BRGDA1) [MIM: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.[35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] Defects in SCN5A are the cause of sick sinus syndrome type 1 (SSS1) [MIM: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.[61] [62] [63] [64] Defects in SCN5A are the cause of familial paroxysmal ventricular fibrillation type 1 (VF1) [MIM: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.[65] [66] Defects in SCN5A may be a cause of sudden infant death syndrome (SIDS) [MIM: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.[67] [68] [69] Defects in SCN5A may be a cause of familial atrial standstill (FAS) [MIM: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.[70] [71] Defects in SCN5A are the cause of cardiomyopathy dilated type 1E (CMD1E) [MIM: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.[72] [73] Defects in SCN5A are the cause of familial atrial fibrillation type 10 (ATFB10) [MIM: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.[74] [75] [76]

Function

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.[77]

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 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[78]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999 Sep;23(1):20-1. PMID:10471492 doi:10.1038/12618
  2. ↑ Tan HL, Bink-Boelkens MT, Bezzina CR, Viswanathan PC, Beaufort-Krol GC, van Tintelen PJ, van den Berg MP, Wilde AA, Balser JR. A sodium-channel mutation causes isolated cardiac conduction disease. Nature. 2001 Feb 22;409(6823):1043-7. PMID:11234013 doi:10.1038/35059090
  3. ↑ Wang DW, Viswanathan PC, Balser JR, George AL Jr, Benson DW. Clinical, genetic, and biophysical characterization of SCN5A mutations associated with atrioventricular conduction block. Circulation. 2002 Jan 22;105(3):341-6. PMID:11804990
  4. ↑ Bezzina CR, Rook MB, Groenewegen WA, Herfst LJ, van der Wal AC, Lam J, Jongsma HJ, Wilde AA, Mannens MM. Compound heterozygosity for mutations (W156X and R225W) in SCN5A associated with severe cardiac conduction disturbances and degenerative changes in the conduction system. Circ Res. 2003 Feb 7;92(2):159-68. PMID:12574143
  5. ↑ Viswanathan PC, Benson DW, Balser JR. A common SCN5A polymorphism modulates the biophysical effects of an SCN5A mutation. J Clin Invest. 2003 Feb;111(3):341-6. PMID:12569159 doi:10.1172/JCI16879
  6. ↑ Meregalli PG, Tan HL, Probst V, Koopmann TT, Tanck MW, Bhuiyan ZA, Sacher F, Kyndt F, Schott JJ, Albuisson J, Mabo P, Bezzina CR, Le Marec H, Wilde AA. Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. Heart Rhythm. 2009 Mar;6(3):341-8. Epub 2008 Nov 11. PMID:19251209 doi:S1547-5271(08)01092-8
  7. ↑ Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999 Sep;23(1):20-1. PMID:10471492 doi:10.1038/12618
  8. ↑ Ye B, Valdivia CR, Ackerman MJ, Makielski JC. A common human SCN5A polymorphism modifies expression of an arrhythmia causing mutation. Physiol Genomics. 2003 Feb 6;12(3):187-93. PMID:12454206 doi:10.1152/physiolgenomics.00117.2002
  9. ↑ Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA, Keating MT. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell. 1995 Mar 10;80(5):805-11. PMID:7889574
  10. ↑ Wang Q, Shen J, Li Z, Timothy K, Vincent GM, Priori SG, Schwartz PJ, Keating MT. Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia. Hum Mol Genet. 1995 Sep;4(9):1603-7. PMID:8541846
  11. ↑ Bennett PB, Yazawa K, Makita N, George AL Jr. Molecular mechanism for an inherited cardiac arrhythmia. Nature. 1995 Aug 24;376(6542):683-5. PMID:7651517 doi:http://dx.doi.org/10.1038/376683a0
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  14. ↑ Benhorin J, Goldmit M, MacCluer JW, Blangero J, Goffen R, Leibovitch A, Rahat A, Wang Q, Medina A, Towbin J, Kerem B. Identification of a new SCN5A mutation, D1840G, associated with the long QT syndrome. Mutations in brief no. 153. Online. Hum Mutat. 1998;12(1):72. PMID:10627139 doi:<72::AID-HUMU17>3.0.CO;2-Z 10.1002/(SICI)1098-1004(1998)12:1<72::AID-HUMU17>3.0.CO;2-Z
  15. ↑ Wattanasirichaigoon D, Vesely MR, Duggal P, Levine JC, Blume ED, Wolff GS, Edwards SB, Beggs AH. Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations. Am J Med Genet. 1999 Oct 29;86(5):470-6. PMID:10508990
  16. ↑ Wei J, Wang DW, Alings M, Fish F, Wathen M, Roden DM, George AL Jr. Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel. Circulation. 1999 Jun 22;99(24):3165-71. PMID:10377081
  17. ↑ Bezzina C, Veldkamp MW, van Den Berg MP, Postma AV, Rook MB, Viersma JW, van Langen IM, Tan-Sindhunata G, Bink-Boelkens MT, van Der Hout AH, Mannens MM, Wilde AA. A single Na(+) channel mutation causing both long-QT and Brugada syndromes. Circ Res. 1999 Dec 3-17;85(12):1206-13. PMID:10590249
  18. ↑ Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000 Sep 5;102(10):1178-85. PMID:10973849
  19. ↑ Schwartz PJ, Priori SG, Dumaine R, Napolitano C, Antzelevitch C, Stramba-Badiale M, Richard TA, Berti MR, Bloise R. A molecular link between the sudden infant death syndrome and the long-QT syndrome. N Engl J Med. 2000 Jul 27;343(4):262-7. PMID:10911008 doi:10.1056/NEJM200007273430405
  20. ↑ Abriel H, Cabo C, Wehrens XH, Rivolta I, Motoike HK, Memmi M, Napolitano C, Priori SG, Kass RS. Novel arrhythmogenic mechanism revealed by a long-QT syndrome mutation in the cardiac Na(+) channel. Circ Res. 2001 Apr 13;88(7):740-5. PMID:11304498
  21. ↑ Rivolta I, Abriel H, Tateyama M, Liu H, Memmi M, Vardas P, Napolitano C, Priori SG, Kass RS. Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes. J Biol Chem. 2001 Aug 17;276(33):30623-30. Epub 2001 Jun 15. PMID:11410597 doi:10.1074/jbc.M104471200
  22. ↑ Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC, Towbin JA. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA. 2001 Nov 14;286(18):2264-9. PMID:11710892
  23. ↑ Clancy CE, Rudy Y. Na(+) channel mutation that causes both Brugada and long-QT syndrome phenotypes: a simulation study of mechanism. Circulation. 2002 Mar 12;105(10):1208-13. PMID:11889015
  24. ↑ Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC, Hohnloser SH, Shimizu W, Schwartz PJ, Stanton M, Murray KT, Norris K, George AL Jr, Roden DM. Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation. 2002 Apr 23;105(16):1943-8. PMID:11997281
  25. ↑ Rivolta I, Clancy CE, Tateyama M, Liu H, Priori SG, Kass RS. A novel SCN5A mutation associated with long QT-3: altered inactivation kinetics and channel dysfunction. Physiol Genomics. 2002 Sep 3;10(3):191-7. PMID:12209021 doi:10.1152/physiolgenomics.00039.2002
  26. ↑ Wehrens XH, Rossenbacker T, Jongbloed RJ, Gewillig M, Heidbuchel H, Doevendans PA, Vos MA, Wellens HJ, Kass RS. A novel mutation L619F in the cardiac Na+ channel SCN5A associated with long-QT syndrome (LQT3): a role for the I-II linker in inactivation gating. Hum Mutat. 2003 May;21(5):552. PMID:12673799 doi:10.1002/humu.9136
  27. ↑ Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005 May;2(5):507-17. PMID:15840476 doi:10.1016/j.hrthm.2005.01.020
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  33. ↑ Makita N, Behr E, Shimizu W, Horie M, Sunami A, Crotti L, Schulze-Bahr E, Fukuhara S, Mochizuki N, Makiyama T, Itoh H, Christiansen M, McKeown P, Miyamoto K, Kamakura S, Tsutsui H, Schwartz PJ, George AL Jr, Roden DM. The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. J Clin Invest. 2008 Jun;118(6):2219-29. doi: 10.1172/JCI34057. PMID:18451998 doi:10.1172/JCI34057
  34. ↑ Shinlapawittayatorn K, Du XX, Liu H, Ficker E, Kaufman ES, Deschenes I. A common SCN5A polymorphism modulates the biophysical defects of SCN5A mutations. Heart Rhythm. 2011 Mar;8(3):455-62. doi: 10.1016/j.hrthm.2010.11.034. Epub 2010, Nov 23. PMID:21109022 doi:10.1016/j.hrthm.2010.11.034
  35. ↑ Schott JJ, Alshinawi C, Kyndt F, Probst V, Hoorntje TM, Hulsbeek M, Wilde AA, Escande D, Mannens MM, Le Marec H. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet. 1999 Sep;23(1):20-1. PMID:10471492 doi:10.1038/12618
  36. ↑ Meregalli PG, Tan HL, Probst V, Koopmann TT, Tanck MW, Bhuiyan ZA, Sacher F, Kyndt F, Schott JJ, Albuisson J, Mabo P, Bezzina CR, Le Marec H, Wilde AA. Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. Heart Rhythm. 2009 Mar;6(3):341-8. Epub 2008 Nov 11. PMID:19251209 doi:S1547-5271(08)01092-8
  37. ↑ Rivolta I, Abriel H, Tateyama M, Liu H, Memmi M, Vardas P, Napolitano C, Priori SG, Kass RS. Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes. J Biol Chem. 2001 Aug 17;276(33):30623-30. Epub 2001 Jun 15. PMID:11410597 doi:10.1074/jbc.M104471200
  38. ↑ Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Ortiz-Lopez R, Wang Z, Antzelevitch C, O'Brien RE, Schulze-Bahr E, Keating MT, Towbin JA, Wang Q. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998 Mar 19;392(6673):293-6. PMID:9521325 doi:10.1038/32675
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  40. ↑ Dumaine R, Towbin JA, Brugada P, Vatta M, Nesterenko DV, Nesterenko VV, Brugada J, Brugada R, Antzelevitch C. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ Res. 1999 Oct 29;85(9):803-9. PMID:10532948
  41. ↑ Makita N, Shirai N, Wang DW, Sasaki K, George AL Jr, Kanno M, Kitabatake A. Cardiac Na(+) channel dysfunction in Brugada syndrome is aggravated by beta(1)-subunit. Circulation. 2000 Jan 4-11;101(1):54-60. PMID:10618304
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  48. ↑ Mohler PJ, Rivolta I, Napolitano C, LeMaillet G, Lambert S, Priori SG, Bennett V. Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes. Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17533-8. Epub 2004 Dec 3. PMID:15579534 doi:10.1073/pnas.0403711101
  49. ↑ Amin AS, Verkerk AO, Bhuiyan ZA, Wilde AA, Tan HL. Novel Brugada syndrome-causing mutation in ion-conducting pore of cardiac Na+ channel does not affect ion selectivity properties. Acta Physiol Scand. 2005 Dec;185(4):291-301. PMID:16266370 doi:10.1111/j.1365-201X.2005.01496.x
  50. ↑ Yokoi H, Makita N, Sasaki K, Takagi Y, Okumura Y, Nishino T, Makiyama T, Kitabatake A, Horie M, Watanabe I, Tsutsui H. Double SCN5A mutation underlying asymptomatic Brugada syndrome. Heart Rhythm. 2005 Mar;2(3):285-92. PMID:15851320 doi:S1547-5271(04)00804-5
  51. ↑ Makiyama T, Akao M, Tsuji K, Doi T, Ohno S, Takenaka K, Kobori A, Ninomiya T, Yoshida H, Takano M, Makita N, Yanagisawa F, Higashi Y, Takeyama Y, Kita T, Horie M. High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations. J Am Coll Cardiol. 2005 Dec 6;46(11):2100-6. Epub 2005 Nov 4. PMID:16325048 doi:S0735-1097(05)02200-X
  52. ↑ Keller DI, Huang H, Zhao J, Frank R, Suarez V, Delacretaz E, Brink M, Osswald S, Schwick N, Chahine M. A novel SCN5A mutation, F1344S, identified in a patient with Brugada syndrome and fever-induced ventricular fibrillation. Cardiovasc Res. 2006 Jun 1;70(3):521-9. Epub 2006 Mar 3. PMID:16616735 doi:10.1016/j.cardiores.2006.02.030
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  54. ↑ Liang P, Liu WL, Hu DY, Li CL, Tao WH, Li L. [Novel SCN5A gene mutations associated with Brugada syndrome: V95I, A1649V and delF1617] Zhonghua Xin Xue Guan Bing Za Zhi. 2006 Jul;34(7):616-9. PMID:17081365
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