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| | ==Human TRPM4 ion channel in lipid nanodiscs in a calcium-bound state== | | ==Human TRPM4 ion channel in lipid nanodiscs in a calcium-bound state== |
| - | <StructureSection load='6bqv' size='340' side='right'caption='[[6bqv]], [[Resolution|resolution]] 3.10Å' scene=''> | + | <SX load='6bqv' size='340' side='right' viewer='molstar' caption='[[6bqv]], [[Resolution|resolution]] 3.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6bqv]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BQV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BQV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6bqv]] 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=6BQV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BQV 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>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.1Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TRPM4, LTRPC4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</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=6bqv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bqv OCA], [http://pdbe.org/6bqv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bqv RCSB], [http://www.ebi.ac.uk/pdbsum/6bqv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bqv 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=6bqv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bqv OCA], [https://pdbe.org/6bqv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6bqv RCSB], [https://www.ebi.ac.uk/pdbsum/6bqv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6bqv ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/TRPM4_HUMAN TRPM4_HUMAN]] Familial progressive cardiac conduction defect;Brugada syndrome. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/TRPM4_HUMAN TRPM4_HUMAN] Familial progressive cardiac conduction defect;Brugada syndrome. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TRPM4_HUMAN TRPM4_HUMAN]] Calcium-activated non selective (CAN) cation channel that mediates membrane depolarization. While it is activated by increase in intracellular Ca(2+), it is impermeable to it. Mediates transport of monovalent cations (Na(+) > K(+) > Cs(+) > Li(+)), leading to depolarize the membrane. It thereby plays a central role in cadiomyocytes, neurons from entorhinal cortex, dorsal root and vomeronasal neurons, endocrine pancreas cells, kidney epithelial cells, cochlea hair cells etc. Participates in T-cell activation by modulating Ca(2+) oscillations after T lymphocyte activation, which is required for NFAT-dependent IL2 production. Involved in myogenic constriction of cerebral arteries. Controls insulin secretion in pancreatic beta-cells. May also be involved in pacemaking or could cause irregular electrical activity under conditions of Ca(2+) overload. Affects T-helper 1 (Th1) and T-helper 2 (Th2) cell motility and cytokine production through differential regulation of calcium signaling and NFATC1 localization. Enhances cell proliferation through up-regulation of the beta-catenin signaling pathway.<ref>PMID:12015988</ref> <ref>PMID:12799367</ref> <ref>PMID:15121803</ref> <ref>PMID:15472118</ref> <ref>PMID:15550671</ref> <ref>PMID:16806463</ref> <ref>PMID:20625999</ref> <ref>PMID:20656926</ref> | + | [https://www.uniprot.org/uniprot/TRPM4_HUMAN TRPM4_HUMAN] Calcium-activated non selective (CAN) cation channel that mediates membrane depolarization. While it is activated by increase in intracellular Ca(2+), it is impermeable to it. Mediates transport of monovalent cations (Na(+) > K(+) > Cs(+) > Li(+)), leading to depolarize the membrane. It thereby plays a central role in cadiomyocytes, neurons from entorhinal cortex, dorsal root and vomeronasal neurons, endocrine pancreas cells, kidney epithelial cells, cochlea hair cells etc. Participates in T-cell activation by modulating Ca(2+) oscillations after T lymphocyte activation, which is required for NFAT-dependent IL2 production. Involved in myogenic constriction of cerebral arteries. Controls insulin secretion in pancreatic beta-cells. May also be involved in pacemaking or could cause irregular electrical activity under conditions of Ca(2+) overload. Affects T-helper 1 (Th1) and T-helper 2 (Th2) cell motility and cytokine production through differential regulation of calcium signaling and NFATC1 localization. Enhances cell proliferation through up-regulation of the beta-catenin signaling pathway.<ref>PMID:12015988</ref> <ref>PMID:12799367</ref> <ref>PMID:15121803</ref> <ref>PMID:15472118</ref> <ref>PMID:15550671</ref> <ref>PMID:16806463</ref> <ref>PMID:20625999</ref> <ref>PMID:20656926</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | Transient receptor potential (TRP) melastatin 4 (TRPM4) is a widely expressed cation channel associated with a variety of cardiovascular disorders. TRPM4 is activated by increased intracellular calcium in a voltage dependent manner, but unlike many other TRP channels is permeable to monovalent cations only. Here we present two structures of full-length human TRPM4 embedded in lipid nanodiscs at ~3A resolution as determined by single particle electron cryo-microscopy. These structures, with and without calcium bound, reveal a general architecture for this major subfamily of TRP channels and a well-defined calcium binding site within the intracellular side of the S1-S4 domain. The structures correspond to two distinct closed states. Calcium binding induces conformational changes that likely prime the channel for voltage-dependent opening.
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| - | Structure of the human TRPM4 ion channel in a lipid nanodisc.,Autzen HE, Myasnikov AG, Campbell MG, Asarnow D, Julius D, Cheng Y Science. 2017 Dec 7. pii: science.aar4510. doi: 10.1126/science.aar4510. PMID:29217581<ref>PMID:29217581</ref>
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| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 6bqv" style="background-color:#fffaf0;"></div>
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| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| - | </StructureSection> | + | </SX> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Asarnow, D]] | + | [[Category: Asarnow D]] |
| - | [[Category: Autzen, H E]] | + | [[Category: Autzen HE]] |
| - | [[Category: Campbell, M G]] | + | [[Category: Campbell MG]] |
| - | [[Category: Cheng, Y]] | + | [[Category: Cheng Y]] |
| - | [[Category: Julius, D]] | + | [[Category: Julius D]] |
| - | [[Category: Myasnikov, A G]] | + | [[Category: Myasnikov AG]] |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: Trp channel]]
| + | |
| - | [[Category: Trpm channel]]
| + | |
| - | [[Category: Trpm4]]
| + | |
| Structural highlights
Disease
TRPM4_HUMAN Familial progressive cardiac conduction defect;Brugada syndrome. The disease is caused by mutations affecting the gene represented in this entry.
Function
TRPM4_HUMAN Calcium-activated non selective (CAN) cation channel that mediates membrane depolarization. While it is activated by increase in intracellular Ca(2+), it is impermeable to it. Mediates transport of monovalent cations (Na(+) > K(+) > Cs(+) > Li(+)), leading to depolarize the membrane. It thereby plays a central role in cadiomyocytes, neurons from entorhinal cortex, dorsal root and vomeronasal neurons, endocrine pancreas cells, kidney epithelial cells, cochlea hair cells etc. Participates in T-cell activation by modulating Ca(2+) oscillations after T lymphocyte activation, which is required for NFAT-dependent IL2 production. Involved in myogenic constriction of cerebral arteries. Controls insulin secretion in pancreatic beta-cells. May also be involved in pacemaking or could cause irregular electrical activity under conditions of Ca(2+) overload. Affects T-helper 1 (Th1) and T-helper 2 (Th2) cell motility and cytokine production through differential regulation of calcium signaling and NFATC1 localization. Enhances cell proliferation through up-regulation of the beta-catenin signaling pathway.[1] [2] [3] [4] [5] [6] [7] [8]
References
- ↑ Launay P, Fleig A, Perraud AL, Scharenberg AM, Penner R, Kinet JP. TRPM4 is a Ca2+-activated nonselective cation channel mediating cell membrane depolarization. Cell. 2002 May 3;109(3):397-407. PMID:12015988
- ↑ Nilius B, Prenen J, Droogmans G, Voets T, Vennekens R, Freichel M, Wissenbach U, Flockerzi V. Voltage dependence of the Ca2+-activated cation channel TRPM4. J Biol Chem. 2003 Aug 15;278(33):30813-20. Epub 2003 Jun 10. PMID:12799367 doi:http://dx.doi.org/10.1074/jbc.M305127200
- ↑ Guinamard R, Chatelier A, Demion M, Potreau D, Patri S, Rahmati M, Bois P. Functional characterization of a Ca(2+)-activated non-selective cation channel in human atrial cardiomyocytes. J Physiol. 2004 Jul 1;558(Pt 1):75-83. Epub 2004 Apr 30. PMID:15121803 doi:http://dx.doi.org/10.1113/jphysiol.2004.063974
- ↑ Earley S, Waldron BJ, Brayden JE. Critical role for transient receptor potential channel TRPM4 in myogenic constriction of cerebral arteries. Circ Res. 2004 Oct 29;95(9):922-9. Epub 2004 Oct 7. PMID:15472118 doi:http://dx.doi.org/01.RES.0000147311.54833.03
- ↑ Launay P, Cheng H, Srivatsan S, Penner R, Fleig A, Kinet JP. TRPM4 regulates calcium oscillations after T cell activation. Science. 2004 Nov 19;306(5700):1374-7. doi: 10.1126/science.1098845. PMID:15550671 doi:http://dx.doi.org/10.1126/science.1098845
- ↑ Cheng H, Beck A, Launay P, Gross SA, Stokes AJ, Kinet JP, Fleig A, Penner R. TRPM4 controls insulin secretion in pancreatic beta-cells. Cell Calcium. 2007 Jan;41(1):51-61. Epub 2006 Jun 27. PMID:16806463 doi:http://dx.doi.org/S0143-4160(06)00105-9
- ↑ Armisen R, Marcelain K, Simon F, Tapia JC, Toro J, Quest AF, Stutzin A. TRPM4 enhances cell proliferation through up-regulation of the beta-catenin signaling pathway. J Cell Physiol. 2011 Jan;226(1):103-9. doi: 10.1002/jcp.22310. PMID:20625999 doi:http://dx.doi.org/10.1002/jcp.22310
- ↑ Weber KS, Hildner K, Murphy KM, Allen PM. Trpm4 differentially regulates Th1 and Th2 function by altering calcium signaling and NFAT localization. J Immunol. 2010 Sep 1;185(5):2836-46. doi: 10.4049/jimmunol.1000880. Epub 2010, Jul 23. PMID:20656926 doi:http://dx.doi.org/10.4049/jimmunol.1000880
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