8dxp: Difference between revisions

</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=8dxp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dxp OCA], [https://pdbe.org/8dxp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dxp RCSB], [https://www.ebi.ac.uk/pdbsum/8dxp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dxp ProSAT]</span></td></tr>

Volume-regulated anion channels (VRACs) mediate volume regulatory Cl(-) and organic solute efflux from vertebrate cells. VRACs are heteromeric assemblies of LRRC8A-E proteins with unknown stoichiometries. Homomeric LRRC8A and LRRC8D channels have a small pore, hexameric structure. However, these channels are either non-functional nor exhibit abnormal regulation and pharmacology, limiting their utility for structure-function analyses. We circumvented these limitations by developing novel homomeric LRRC8 chimeric channels with functional properties consistent with those of native VRAC/LRRC8 channels. We demonstrate here that the LRRC8C-LRRC8A(IL1(25)) chimera comprising LRRC8C and 25 amino acids unique to the first intracellular loop (IL1) of LRRC8A has a heptameric structure like that of homologous pannexin channels. Unlike homomeric LRRC8A and LRRC8D channels, heptameric LRRC8C-LRRC8A(IL1(25)) channels have a large-diameter pore similar to that estimated for native VRACs, exhibit normal DCPIB pharmacology, and have higher permeability to large organic anions. Lipid-like densities are located between LRRC8C-LRRC8A(IL1(25)) subunits and occlude the channel pore. Our findings provide new insights into VRAC/LRRC8 channel structure and suggest that lipids may play important roles in channel gating and regulation.

Cryo-EM structures of a LRRC8 chimera with native functional properties reveal heptameric assembly.,Takahashi H, Yamada T, Denton JS, Strange K, Karakas E Elife. 2023 Mar 10;12:e82431. doi: 10.7554/eLife.82431. PMID:36897307<ref>PMID:36897307</ref>