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==Voltage-gated sodium channel 1.5 C-terminal domain in complex with FGF12B and Ca2+/calmodulin==
==Voltage-gated sodium channel 1.5 C-terminal domain in complex with FGF12B and Ca2+/calmodulin==
<StructureSection load='4jq0' size='340' side='right' caption='[[4jq0]], [[Resolution|resolution]] 3.84&Aring;' scene=''>
<StructureSection load='4jq0' size='340' side='right'caption='[[4jq0]], [[Resolution|resolution]] 3.84&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4jq0]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JQ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JQ0 FirstGlance]. <br>
<table><tr><td colspan='2'>[[4jq0]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JQ0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JQ0 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.84&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4jpz|4jpz]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4jq0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jq0 OCA], [http://pdbe.org/4jq0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4jq0 RCSB], [http://www.ebi.ac.uk/pdbsum/4jq0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4jq0 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=4jq0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jq0 OCA], [https://pdbe.org/4jq0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jq0 RCSB], [https://www.ebi.ac.uk/pdbsum/4jq0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jq0 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/SCN5A_HUMAN SCN5A_HUMAN]] Defects in SCN5A are a cause of progressive familial heart block type 1A (PFHB1A) [MIM:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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:[http://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 ==
[[http://www.uniprot.org/uniprot/FGF12_HUMAN FGF12_HUMAN]] Probably involved in nervous system development and function. [[http://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/FGF12_HUMAN FGF12_HUMAN] Probably involved in nervous system development and function.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Ca(2+) regulates voltage-gated Na(+) (NaV) channels, and perturbed Ca(2+) regulation of NaV function is associated with epilepsy syndromes, autism and cardiac arrhythmias. Understanding the disease mechanisms, however, has been hindered by a lack of structural information and competing models for how Ca(2+) affects NaV channel function. Here we report the crystal structures of two ternary complexes of a human NaV cytosolic C-terminal domain (CTD), a fibroblast growth factor homologous factor and Ca(2+)/calmodulin (Ca(2+)/CaM). These structures rule out direct binding of Ca(2+) to the NaV CTD and uncover new contacts between CaM and the NaV CTD. Probing these new contacts with biochemical and functional experiments allows us to propose a mechanism by which Ca(2+) could regulate NaV channels. Further, our model provides hints towards understanding the molecular basis of the neurologic disorders and cardiac arrhythmias caused by NaV channel mutations.
 
Structural analyses of Ca(2+)/CaM interaction with NaV channel C-termini reveal mechanisms of calcium-dependent regulation.,Wang C, Chung BC, Yan H, Wang HG, Lee SY, Pitt GS Nat Commun. 2014 Sep 18;5:4896. doi: 10.1038/ncomms5896. PMID:25232683<ref>PMID:25232683</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4jq0" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Calmodulin|Calmodulin]]
*[[Calmodulin 3D structures|Calmodulin 3D structures]]
*[[Ion channels|Ion channels]]
*[[Fibroblast growth factor 3D structures|Fibroblast growth factor 3D structures]]
== References ==
*[[Ion channels 3D structures|Ion channels 3D structures]]
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Chung, B C]]
[[Category: Homo sapiens]]
[[Category: Lee, S Y]]
[[Category: Large Structures]]
[[Category: Pitt, G S]]
[[Category: Chung BC]]
[[Category: Wang, C]]
[[Category: Lee SY]]
[[Category: Wang, H G]]
[[Category: Pitt GS]]
[[Category: Yan, H]]
[[Category: Wang C]]
[[Category: Ef hand]]
[[Category: Wang HG]]
[[Category: Ion channel]]
[[Category: Yan H]]
[[Category: Membrane]]
[[Category: Transport protein]]

Latest revision as of 15:05, 1 March 2024

Voltage-gated sodium channel 1.5 C-terminal domain in complex with FGF12B and Ca2+/calmodulinVoltage-gated sodium channel 1.5 C-terminal domain in complex with FGF12B and Ca2+/calmodulin

Structural highlights

4jq0 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.84Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FGF12_HUMAN Probably involved in nervous system development and function.

See Also

4jq0, resolution 3.84Å

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OCA