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2mng

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Revision as of 17:23, 15 August 2018

Apo Structure of human HCN4 CNBD solved by NMR

Structural highlights

2mng is a 1 chain structure with sequence from Human. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:	HCN4 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[HCN4_HUMAN] Sick sinus syndrome;Brugada syndrome. Sick sinus syndrome 2 (SSS2) [MIM:163800]: 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. SSS2 onset is in utero or at birth. Note=The disease is caused by mutations affecting the gene represented in this entry.^[1] ^[2] Brugada syndrome 8 (BRGDA8) [MIM:613123]: A 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, the individual will faint and may die in a few minutes if the heart is not reset. Note=The disease is caused by mutations affecting the gene represented in this entry.^[3]

Function

[HCN4_HUMAN] Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. May contribute to the native pacemaker currents in heart (If) and in neurons (Ih). Activated by cAMP. May mediate responses to sour stimuli.^[4] ^[5]

Publication Abstract from PubMed

Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels control neuronal and cardiac electrical rhythmicity. There are four homologous isoforms (HCN1-4) sharing a common multidomain architecture that includes an N-terminal transmembrane tetrameric ion channel followed by a cytoplasmic "C-linker," which connects a more distal cAMP-binding domain (CBD) to the inner pore. Channel opening is primarily stimulated by transmembrane elements that sense membrane hyperpolarization, although cAMP reduces the voltage required for HCN activation by promoting tetramerization of the intracellular C-linker, which in turn relieves auto-inhibition of the inner pore gate. Although binding of cAMP has been proposed to relieve auto-inhibition by affecting the structure of the C-linker and CBD, the nature and extent of these cAMP-dependent changes remain limitedly explored. Here, we used NMR to probe the changes caused by the binding of cAMP and of cCMP, a partial agonist, to the apo-CBD of HCN4. Our data indicate that the CBD exists in a dynamic two-state equilibrium, whose position as gauged by NMR chemical shifts correlates with the V(1/2) voltage measured through electrophysiology. In the absence of cAMP, the most populated CBD state leads to steric clashes with the activated or "tetrameric" C-linker, which becomes energetically unfavored. The steric clashes of the apo tetramer are eliminated either by cAMP binding, which selects for a CBD state devoid of steric clashes with the tetrameric C-linker and facilitates channel opening, or by a transition of apo-HCN to monomers or dimer of dimers, in which the C-linker becomes less structured, and channel opening is not facilitated.

A mechanism for the auto-inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel opening and its relief by cAMP.,Akimoto M, Zhang Z, Boulton S, Selvaratnam R, VanSchouwen B, Gloyd M, Accili EA, Lange OF, Melacini G J Biol Chem. 2014 Aug 8;289(32):22205-20. doi: 10.1074/jbc.M114.572164. Epub 2014, May 30. PMID:24878962^[6]

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

References

↑ Milanesi R, Baruscotti M, Gnecchi-Ruscone T, DiFrancesco D. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N Engl J Med. 2006 Jan 12;354(2):151-7. PMID:16407510 doi:10.1056/NEJMoa052475
↑ Laish-Farkash A, Glikson M, Brass D, Marek-Yagel D, Pras E, Dascal N, Antzelevitch C, Nof E, Reznik H, Eldar M, Luria D. A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews. J Cardiovasc Electrophysiol. 2010 Dec;21(12):1365-72. doi:, 10.1111/j.1540-8167.2010.01844.x. PMID:20662977 doi:10.1111/j.1540-8167.2010.01844.x
↑ Ueda K, Hirano Y, Higashiuesato Y, Aizawa Y, Hayashi T, Inagaki N, Tana T, Ohya Y, Takishita S, Muratani H, Hiraoka M, Kimura A. Role of HCN4 channel in preventing ventricular arrhythmia. J Hum Genet. 2009 Feb;54(2):115-21. doi: 10.1038/jhg.2008.16. Epub 2009 Jan 23. PMID:19165230 doi:10.1038/jhg.2008.16
↑ Ludwig A, Zong X, Stieber J, Hullin R, Hofmann F, Biel M. Two pacemaker channels from human heart with profoundly different activation kinetics. EMBO J. 1999 May 4;18(9):2323-9. PMID:10228147 doi:10.1093/emboj/18.9.2323
↑ Seifert R, Scholten A, Gauss R, Mincheva A, Lichter P, Kaupp UB. Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis. Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9391-6. PMID:10430953
↑ Akimoto M, Zhang Z, Boulton S, Selvaratnam R, VanSchouwen B, Gloyd M, Accili EA, Lange OF, Melacini G. A mechanism for the auto-inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel opening and its relief by cAMP. J Biol Chem. 2014 Aug 8;289(32):22205-20. doi: 10.1074/jbc.M114.572164. Epub 2014, May 30. PMID:24878962 doi:http://dx.doi.org/10.1074/jbc.M114.572164

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2mng"

@@ Line 1: / Line 1: @@
 ==Apo Structure of human HCN4 CNBD solved by NMR==
 <StructureSection load='2mng' size='340' side='right' caption='[[2mng]], [[NMR_Ensembles_of_Models | 10 NMR models]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2mng]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MNG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2MNG FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2mng]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MNG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2MNG FirstGlance]. <br>
-</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=2mng FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mng OCA], [http://pdbe.org/2mng PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2mng RCSB], [http://www.ebi.ac.uk/pdbsum/2mng PDBsum]</span></td></tr>
+</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HCN4 ([http://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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2mng FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mng OCA], [http://pdbe.org/2mng PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2mng RCSB], [http://www.ebi.ac.uk/pdbsum/2mng PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2mng ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 25: / Line 27: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Accili, E A]]
 [[Category: Akimoto, M]]

2mng

From Proteopedia

Revision as of 17:23, 15 August 2018

Apo Structure of human HCN4 CNBD solved by NMR

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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