1.A.25.3.1 The volume-regulated Anion Channel, VRAC, or volume-sensitive outward rectifying anion channel, VSOR. It is also called the SWELL1 protein. It consists of the leucine-rich repeat-containing protein 8A, with an N-terminal pannexin-like domain, LRRC8A, together with other LRRC8 subunits (B, C, D and E). The first two TMSs of the 4 TMS LRRC8 proteins appear as DUF3733 in CDD (Abascal and Zardoya, 2012). The C-terminal soluble domain shows sequence similarity to the heme-binding protein, Shv, and pollen-specific leucine-rich repeat extension-like proteins (3.A.20.1.1). The volume-regulated anion channel, VRAC, has
LRRC8A as a VRAC component. It forms heteromers with other LRRC8 membrane proteins (Voss et al. 2014). Genomic disruption of LRRC8A ablated VRAC
currents. Cells with disruption of all five LRRC8 genes required LRRC8A
cotransfection with other LRRC8 isoforms to reconstitute VRAC currents.
The isoform combination determined the VRAC inactivation kinetics. Taurine
flux and regulatory volume decrease also depended on LRRC8 proteins. Thus, VRAC defines a class of anion channels, suggesting that
VRAC is identical to the volume-sensitive organic osmolyte/anion channel
VSOAC, and explains the heterogeneity of native VRAC currents (Voss et al. 2014). Point mutations in two amino-acyl residues (Lys98 and Asp100 in LRRC8A and equivalent
residues in LRRC8C and -E) upon charge reversal, alter the kinetics and voltage-dependence of inactivation (Ullrich et al. 2016). Using cryo-electron microscopy and X-ray crystallography, Deneka et al. 2018 and Kasuya et al. 2018 determined the structures of a homomeric channel of the obligatory
subunit LRRC8A. This protein conducts ions and has
properties in common with endogenous heteromeric channels. Its modular
structure consists of a transmembrane pore domain followed by a
cytoplasmic leucine-rich repeat domain. The transmembrane domain, which
is structurally related to connexins, is wide towards the cytoplasm but
constricted on the outside by a structural unit that acts as a
selectivity filter. An excess of basic residues in the filter and
throughout the pore attracts anions by electrostatic interaction (Deneka et al. 2018). The structure shows a hexameric assembly, and the transmembrane region features a topology similar to gap junction channels. The LRR region, with 15 leucine-rich repeats, forms a long, twisted arc. The channel pore is located along the central axis and constricted on the extracellular side, where highly conserved polar and charged residues at the tip of the extracellular helix contribute to the permeability to anions and other osmolytes. Two structural populations were identified, corresponding to compact and relaxed conformations. Comparing the two conformations suggests that the LRR region is flexible and mobile with rigid-body motions, which might be implicated in structural transitions on pore opening (Kasuya et al. 2018). VRAC is inhibited by Tamoxifen and Mefloquine (Lee et al. 2017). The intracellular loop connecting TMSs 2 and 3 of LRRC8A and the first extracellular loop connecting transmembrane domains 1 and 2 of LRRC8C, LRRC8D, or LRRC8E are essential for VRAC activity (Yamada and Strange 2018). The N termini of the LRRC8 subunits may line the cytoplasmic portion of the VRAC pore, possibly by folding back into the ion permeation pathway (Zhou et al. 2018). On the adipocyte plasma membrane, the SWELL1-/LRRC8 channel complex activates in response to increases in adipocyte volume in the context of obesity. SWELL1 is required for insulin-PI3K-AKT2 signalling to regulate adipocyte growth and systemic glycaemia (Gunasekar et al. 2019). Activation of Swell1 in microglia suppresses neuroinflammation and reduces brain damage in ischemic stroke (Chen et al. 2023).
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Accession Number: | Q6NSJ5 |
Protein Name: | Leucine-rich repeat-containing protein 8E |
Length: | 796 |
Molecular Weight: | 90247.00 |
Species: | Homo sapiens (Human) [9606] |
Number of TMSs: | 4 |
Location1 / Topology2 / Orientation3: |
Membrane1 / Multi-pass membrane protein2 |
Substrate |
anion |
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1: MIPVAEFKQF TEQQPAFKVL KPWWDVLAEY LTVAMLMIGV FGCTLQVTQD KIICLPNHEL
61: QENLSEAPCQ QLLPRGIPEQ IGALQEVKGL KNNLDLQQYS FINQLCYETA LHWYAKYFPY
121: LVVIHTLIFM VCTSFWFKFP GTSSKIEHFI SILGKCFDSP WTTRALSEVS GENQKGPAAT
181: ERAAATIVAM AGTGPGKAGE GEKEKVLAEP EKVVTEPPVV TLLDKKEGEQ AKALFEKVKK
241: FRMHVEEGDI LYTMYIRQTV LKVCKFLAIL VYNLVYVEKI SFLVACRVET SEVTGYASFC
301: CNHTKAHLFS KLAFCYISFV CIYGLTCIYT LYWLFHRPLK EYSFRSVREE TGMGDIPDVK
361: NDFAFMLHLI DQYDSLYSKR FAVFLSEVSE SRLKQLNLNH EWTPEKLRQK LQRNAAGRLE
421: LALCMLPGLP DTVFELSEVE SLRLEAICDI TFPPGLSQLV HLQELSLLHS PARLPFSLQV
481: FLRDHLKVMR VKCEELREVP LWVFGLRGLE ELHLEGLFPQ ELARAATLES LRELKQLKVL
541: SLRSNAGKVP ASVTDVAGHL QRLSLHNDGA RLVALNSLKK LAALRELELV ACGLERIPHA
601: VFSLGALQEL DLKDNHLRSI EEILSFQHCR KLVTLRLWHN QIAYVPEHVR KLRSLEQLYL
661: SYNKLETLPS QLGLCSGLRL LDVSHNGLHS LPPEVGLLQN LQHLALSYNA LEALPEELFF
721: CRKLRTLLLG DNQLSQLSPH VGALRALSRL ELKGNRLEAL PEELGNCGGL KKAGLLVEDT
781: LYQGLPAEVR DKMEEE