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==Structure of human Volume Regulated Anion Channel composed of SWELL1 (LRRC8A)==
<SX load='6djb' size='340' side='right' viewer='molstar' caption='[[6djb]], [[Resolution|resolution]] 4.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6djb]] is a 6 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=6DJB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DJB 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]] 4.4&#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=6djb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6djb OCA], [https://pdbe.org/6djb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6djb RCSB], [https://www.ebi.ac.uk/pdbsum/6djb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6djb ProSAT]</span></td></tr>
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== Disease ==
[https://www.uniprot.org/uniprot/LRC8A_HUMAN LRC8A_HUMAN] Autosomal agammaglobulinemia. The disease is caused by mutations affecting the gene represented in this entry. A chromosomal aberration involving LRRC8 has been found in a patient with congenital agammaglobulinemia. Translocation t(9;20)(q33.2;q12). The translocation truncates the LRRC8 gene, resulting in deletion of the eighth, ninth, and half of the seventh LRR domains.
== Function ==
[https://www.uniprot.org/uniprot/LRC8A_HUMAN LRC8A_HUMAN] 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 (PubMed:24725410, PubMed:24790029, PubMed:26530471, PubMed:26824658, PubMed:28193731, PubMed:29769723). The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (PubMed:24725410, PubMed:24790029, PubMed:26530471, PubMed:26824658, PubMed:28193731). Mediates efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress (PubMed:28193731). LRRC8A and LRRC8D are required for the uptake of the drug cisplatin (PubMed:26530471). Required for in vivo channel activity, together with at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition (PubMed:24790029, PubMed:26824658, PubMed:28193731). Can form functional channels by itself (in vitro) (PubMed:26824658). Involved in B-cell development: required for the pro-B cell to pre-B cell transition (PubMed:14660746). Also required for T-cell development (By similarity).[UniProtKB:Q80WG5]<ref>PMID:14660746</ref> <ref>PMID:24725410</ref> <ref>PMID:24790029</ref> <ref>PMID:26530471</ref> <ref>PMID:26824658</ref> <ref>PMID:28193731</ref> <ref>PMID:29769723</ref> 
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== Publication Abstract from PubMed ==
SWELL1 (LRRC8A) is the only essential subunit of the Volume Regulated Anion Channel (VRAC), which regulates cellular volume homeostasis and is activated by hypotonic solutions. SWELL1, together with four other LRRC8 family members, potentially forms a vastly heterogeneous cohort of VRAC channels with different properties; however, SWELL1 alone is also functional. Here, we report a high-resolution cryo-electron microscopy structure of full-length human homo-hexameric SWELL1. The structure reveals a trimer of dimers assembly with symmetry mismatch between the pore-forming domain and the cytosolic leucine-rich repeat (LRR) domains. Importantly, mutational analysis demonstrates that a charged residue at the narrowest constriction of the homomeric channel is an important pore determinant of heteromeric VRAC. Additionally, a mutation in the flexible N-terminal portion of SWELL1 affects pore properties, suggesting a putative link between intracellular structures and channel regulation. This structure provides a scaffold for further dissecting the heterogeneity and mechanism of activation of VRAC.

Structure of the human volume regulated anion channel.,Kefauver JM, Saotome K, Dubin AE, Pallesen J, Cottrell CA, Cahalan SM, Qiu Z, Hong G, Crowley CS, Whitwam T, Lee WH, Ward AB, Patapoutian A Elife. 2018 Aug 10;7. pii: 38461. doi: 10.7554/eLife.38461. PMID:30095067<ref>PMID:30095067</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6djb" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ion channels 3D structures|Ion channels 3D structures]]
== References ==
<references/>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cottrell CA]]
[[Category: Kefauver JM]]
[[Category: Pallesen J]]
[[Category: Patapoutian A]]
[[Category: Saotome K]]
[[Category: Ward AB]]