6djb

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Structure of human Volume Regulated Anion Channel composed of SWELL1 (LRRC8A)

Structural highlights

6djb is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 4.4Å
Experimental data:Check to display Experimental Data
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

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

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][1] [2] [3] [4] [5] [6] [7]

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[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ 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
  2. ↑ Qiu Z, Dubin AE, Mathur J, Tu B, Reddy K, Miraglia LJ, Reinhardt J, Orth AP, Patapoutian A. SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel. Cell. 2014 Apr 10;157(2):447-458. doi: 10.1016/j.cell.2014.03.024. PMID:24725410 doi:http://dx.doi.org/10.1016/j.cell.2014.03.024
  3. ↑ Voss FK, Ullrich F, Munch J, Lazarow K, Lutter D, Mah N, Andrade-Navarro MA, von Kries JP, Stauber T, Jentsch TJ. Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC. Science. 2014 May 9;344(6184):634-8. doi: 10.1126/science.1252826. Epub 2014 Apr , 10. PMID:24790029 doi:http://dx.doi.org/10.1126/science.1252826
  4. ↑ Planells-Cases R, Lutter D, Guyader C, Gerhards NM, Ullrich F, Elger DA, Kucukosmanoglu A, Xu G, Voss FK, Reincke SM, Stauber T, Blomen VA, Vis DJ, Wessels LF, Brummelkamp TR, Borst P, Rottenberg S, Jentsch TJ. Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs. EMBO J. 2015 Dec 14;34(24):2993-3008. doi: 10.15252/embj.201592409. Epub 2015 Nov, 3. PMID:26530471 doi:http://dx.doi.org/10.15252/embj.201592409
  5. ↑ Syeda R, Qiu Z, Dubin AE, Murthy SE, Florendo MN, Mason DE, Mathur J, Cahalan SM, Peters EC, Montal M, Patapoutian A. LRRC8 Proteins Form Volume-Regulated Anion Channels that Sense Ionic Strength. Cell. 2016 Jan 28;164(3):499-511. doi: 10.1016/j.cell.2015.12.031. PMID:26824658 doi:http://dx.doi.org/10.1016/j.cell.2015.12.031
  6. ↑ Lutter D, Ullrich F, Lueck JC, Kempa S, Jentsch TJ. Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels. J Cell Sci. 2017 Mar 15;130(6):1122-1133. doi: 10.1242/jcs.196253. Epub 2017 Feb , 13. PMID:28193731 doi:http://dx.doi.org/10.1242/jcs.196253
  7. ↑ Deneka D, Sawicka M, Lam AKM, Paulino C, Dutzler R. Structure of a volume-regulated anion channel of the LRRC8 family. Nature. 2018 May 16. pii: 10.1038/s41586-018-0134-y. doi:, 10.1038/s41586-018-0134-y. PMID:29769723 doi:http://dx.doi.org/10.1038/s41586-018-0134-y
  8. ↑ 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. Structure of the human volume regulated anion channel. Elife. 2018 Aug 10;7. pii: 38461. doi: 10.7554/eLife.38461. PMID:30095067 doi:http://dx.doi.org/10.7554/eLife.38461

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6djb, resolution 4.40Å

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