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| | <SX load='6nzw' size='340' side='right' viewer='molstar' caption='[[6nzw]], [[Resolution|resolution]] 3.21Å' scene=''> | | <SX load='6nzw' size='340' side='right' viewer='molstar' caption='[[6nzw]], [[Resolution|resolution]] 3.21Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6nzw]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NZW OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6NZW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6nzw]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NZW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NZW FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L9Y:4-{[(2S)-2-butyl-6,7-dichloro-2-cyclopentyl-1-oxo-2,3-dihydro-1H-inden-5-yl]oxy}butanoic+acid'>L9Y</scene>, <scene name='pdbligand=POV:(2S)-3-(HEXADECANOYLOXY)-2-[(9Z)-OCTADEC-9-ENOYLOXY]PROPYL+2-(TRIMETHYLAMMONIO)ETHYL+PHOSPHATE'>POV</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]] 3.21Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Lrrc8a, Lrrc8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L9Y:4-[[(2~{S})-2-butyl-6,7-bis(chloranyl)-2-cyclopentyl-1-oxidanylidene-3~{H}-inden-5-yl]oxy]butanoic+acid'>L9Y</scene>, <scene name='pdbligand=POV:(2S)-3-(HEXADECANOYLOXY)-2-[(9Z)-OCTADEC-9-ENOYLOXY]PROPYL+2-(TRIMETHYLAMMONIO)ETHYL+PHOSPHATE'>POV</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6nzw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nzw OCA], [http://pdbe.org/6nzw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nzw RCSB], [http://www.ebi.ac.uk/pdbsum/6nzw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nzw 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=6nzw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nzw OCA], [https://pdbe.org/6nzw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nzw RCSB], [https://www.ebi.ac.uk/pdbsum/6nzw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nzw ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/LRC8A_MOUSE LRC8A_MOUSE]] Essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes. The VRAC channel conducts iodide better than chloride and may also conduct organic osmolytes like taurine. Required for channel activity, together with at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition. Can form functional channels by itself (in vitro) (By similarity). Involved in B-cell development: required for the pro-B cell to pre-B cell transition (PubMed:14660746, PubMed:24752297). Also required for T-cell development (PubMed:24752297).[UniProtKB:Q8IWT6]<ref>PMID:14660746</ref> <ref>PMID:24752297</ref> | + | [https://www.uniprot.org/uniprot/LRC8A_MOUSE LRC8A_MOUSE] Essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes. The VRAC channel conducts iodide better than chloride and may also conduct organic osmolytes like taurine. Required for channel activity, together with at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition. Can form functional channels by itself (in vitro) (By similarity). Involved in B-cell development: required for the pro-B cell to pre-B cell transition (PubMed:14660746, PubMed:24752297). Also required for T-cell development (PubMed:24752297).[UniProtKB:Q8IWT6]<ref>PMID:14660746</ref> <ref>PMID:24752297</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 27: |
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| | </SX> | | </SX> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Mus musculus]] |
| - | [[Category: Brohawn, S G]] | + | [[Category: Brohawn SG]] |
| - | [[Category: Hite, R K]] | + | [[Category: Hite RK]] |
| - | [[Category: Kern, D M]] | + | [[Category: Kern DM]] |
| - | [[Category: Ion channel]]
| + | |
| - | [[Category: Membrane protein]]
| + | |
| - | [[Category: Volume-regulation]]
| + | |
| Structural highlights
Function
LRC8A_MOUSE Essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes. The VRAC channel conducts iodide better than chloride and may also conduct organic osmolytes like taurine. Required for channel activity, together with at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition. Can form functional channels by itself (in vitro) (By similarity). Involved in B-cell development: required for the pro-B cell to pre-B cell transition (PubMed:14660746, PubMed:24752297). Also required for T-cell development (PubMed:24752297).[UniProtKB:Q8IWT6][1] [2]
Publication Abstract from PubMed
Hypoosmotic conditions activate volume-regulated anion channels in vertebrate cells. These channels are formed by leucine-rich repeat-containing protein 8 (LRRC8) family members and contain LRRC8A in homo- or hetero-hexameric assemblies. Here, we present single-particle cryo-electron microscopy structures of Mus musculus LRRC8A in complex with the inhibitor DCPIB reconstituted in lipid nanodiscs. DCPIB plugs the channel like a cork in a bottle - binding in the extracellular selectivity filter and sterically occluding ion conduction. Constricted and expanded structures reveal coupled dilation of cytoplasmic LRRs and the channel pore, suggesting a mechanism for channel gating by internal stimuli. Conformational and symmetry differences between LRRC8A structures determined in detergent micelles and lipid bilayers related to reorganization of intersubunit lipid binding sites demonstrate a critical role for the membrane in determining channel structure. These results provide insight into LRRC8 gating and inhibition and the role of lipids in the structure of an ionic-strength sensing ion channel.
Cryo-EM structures of the DCPIB-inhibited volume-regulated anion channel LRRC8A in lipid nanodiscs.,Kern DM, Oh S, Hite RK, Brohawn SG Elife. 2019 Feb 18;8. pii: 42636. doi: 10.7554/eLife.42636. PMID:30775971[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Sawada A, Takihara Y, Kim JY, Matsuda-Hashii Y, Tokimasa S, Fujisaki H, Kubota K, Endo H, Onodera T, Ohta H, Ozono K, Hara J. A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans. J Clin Invest. 2003 Dec;112(11):1707-13. doi: 10.1172/JCI18937. PMID:14660746 doi:http://dx.doi.org/10.1172/JCI18937
- ↑ Kumar L, Chou J, Yee CS, Borzutzky A, Vollmann EH, von Andrian UH, Park SY, Hollander G, Manis JP, Poliani PL, Geha RS. Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function. J Exp Med. 2014 May 5;211(5):929-42. doi: 10.1084/jem.20131379. Epub 2014 Apr 21. PMID:24752297 doi:http://dx.doi.org/10.1084/jem.20131379
- ↑ Kern DM, Oh S, Hite RK, Brohawn SG. Cryo-EM structures of the DCPIB-inhibited volume-regulated anion channel LRRC8A in lipid nanodiscs. Elife. 2019 Feb 18;8. pii: 42636. doi: 10.7554/eLife.42636. PMID:30775971 doi:http://dx.doi.org/10.7554/eLife.42636
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