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6o00

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apo-LRRC8A in MSP2N2 nanodisc constricted state

6o00, resolution 4.18Å

Structural highlights

6o00 is a 6 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:	6nzw, 6nzz
Gene:	Lrrc8a, Lrrc8 (LK3 transgenic mice)
Experimental data:	Check to display Experimental Data
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.

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

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6o00"

@@ Line 3: / Line 3: @@
 <SX load='6o00' size='340' side='right' viewer='molstar' caption='[[6o00]], [[Resolution|resolution]] 4.18&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6o00]] 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=6O00 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6O00 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6o00]] 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=6O00 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6O00 FirstGlance]. <br>
 </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6nzw|6nzw]], [[6nzz|6nzz]]</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='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=6o00 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o00 OCA], [http://pdbe.org/6o00 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o00 RCSB], [http://www.ebi.ac.uk/pdbsum/6o00 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o00 ProSAT]</span></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=6o00 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6o00 OCA], [http://pdbe.org/6o00 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6o00 RCSB], [http://www.ebi.ac.uk/pdbsum/6o00 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6o00 ProSAT]</span></td></tr>
 </table>
 == Function ==

6o00

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Current revision

apo-LRRC8A in MSP2N2 nanodisc constricted state

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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