8DXN

Structure of LRRC8C-LRRC8A(IL125) Chimera, Class 1

Summary for 8DXN

• Entry DOI: 10.2210/pdb8dxn/pdb
• EMDB information: 27770
• Descriptor: Volume-regulated anion channel subunit LRRC8C,Volume-regulated anion channel subunit LRRC8A (1 entity in total)
• Functional Keywords: lrrc8c, lrrc8a, swell, vrac, chimera, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 663233.86

Authors

Takahashi, H.,Yamada, T.,Denton, J.S.,Strange, K.,Karakas, E. (deposition date: 2022-08-02, release date: 2023-03-22, Last modification date: 2024-10-30)

Primary citation

Takahashi, H.,Yamada, T.,Denton, J.S.,Strange, K.,Karakas, E.
Cryo-EM structures of a LRRC8 chimera with native functional properties reveal heptameric assembly.
Elife, 12:-, 2023

PubMed Abstract: 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 or 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) 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) 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) 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.

PubMed: 36897307
DOI: 10.7554/eLife.82431

Experimental method

ELECTRON MICROSCOPY (3.4 Å)