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==Cryo-EM structure of the human inward-rectifier potassium 2.1 channel (Kir2.1) - R312H mutant==
<StructureSection load='8qql' size='340' side='right'caption='[[8qql]], [[Resolution|resolution]] 6.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8qql]] is a 4 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=8QQL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8QQL FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 6&#8491;</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=8qql FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8qql OCA], [https://pdbe.org/8qql PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8qql RCSB], [https://www.ebi.ac.uk/pdbsum/8qql PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8qql ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/KCNJ2_HUMAN KCNJ2_HUMAN] Andersen-Tawil syndrome;Familial short QT syndrome;Familial atrial fibrillation. The disease is caused by variants affecting the gene represented in this entry.  The disease is caused by variants affecting the gene represented in this entry.  The disease is caused by variants affecting the gene represented in this entry.
== Function ==
[https://www.uniprot.org/uniprot/KCNJ2_HUMAN KCNJ2_HUMAN] Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it (PubMed:36149965, PubMed:7590287, PubMed:9490857). Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages (PubMed:7590287, PubMed:7696590). The inward rectification is mainly due to the blockage of outward current by internal magnesium (PubMed:9490857). Can be blocked by extracellular barium or cesium (PubMed:7590287, PubMed:7696590). Probably participates in establishing action potential waveform and excitability of neuronal and muscle tissues (PubMed:7590287, PubMed:7696590, PubMed:7840300).<ref>PMID:11371347</ref> <ref>PMID:15761194</ref> <ref>PMID:15922306</ref> <ref>PMID:16571646</ref> <ref>PMID:17324964</ref> <ref>PMID:36149965</ref> <ref>PMID:7590287</ref> <ref>PMID:7696590</ref> <ref>PMID:7840300</ref> <ref>PMID:8821791</ref> <ref>PMID:9490857</ref> <ref>PMID:9533862</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Inwardly rectifying potassium (Kir) channels play a pivotal role in physiology by establishing, maintaining, and regulating the resting membrane potential of the cells, particularly contributing to the cellular repolarization of many excitable cells. Dysfunction in Kir2.1 channels is implicated in several chronic and debilitating human diseases for which there are currently no effective treatments. Specifically, Kir2.1-R312H and Kir2.1-C154Y mutations are associated with Andersen-Tawil syndrome (ATS) in humans. We have investigated the impact of these two mutants in the trafficking of the channel to the cell membrane and function in Xenopus laevis oocytes. Despite both mutations being trafficked to the cell membrane at different extents and capable of binding PIP(2) (phosphatidylinositol-4,5-bisphosphate), the main modulator for channel activity, they resulted in defective channels that do not display K(+) current, albeit through different molecular mechanisms. Coexpression studies showed that R312H and C154Y are expressed and associated with the WT subunits. While WT subunits could rescue R312H dysfunction, the presence of a unique C154Y subunit disrupts the function of the entire complex, which is a typical feature of mutations with a dominant-negative effect. Molecular dynamics simulations showed that Kir2.1-C154Y mutation induces a loss in the structural plasticity of the selectivity filter, impairing the K(+) flow. In addition, the cryo-EM structure of the Kir2.1-R312H mutant has been reconstructed. This study identified the molecular mechanisms by which two ATS-causing mutations impact Kir2.1 channel function and provide valuable insights that can guide potential strategies for the development of future therapeutic interventions for ATS.

Biochemical, biophysical, and structural investigations of two mutants (C154Y and R312H) of the human Kir2.1 channel involved in the Andersen-Tawil syndrome.,Zuniga D, Zoumpoulakis A, Veloso RF, Peverini L, Shi S, Pozza A, Kugler V, Bonnete F, Bouceba T, Wagner R, Corringer PJ, Fernandes CAH, Venien-Bryan C FASEB J. 2024 Nov 15;38(21):e70146. doi: 10.1096/fj.202401567R. PMID:39520289<ref>PMID:39520289</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8qql" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Fernandes CAH]]
[[Category: Venien-Bryan C]]
[[Category: Zuniga D]]