Structure of a volume-regulated heteromeric LRRC8A/C channel

Volume-regulated anion channels (VRACs) participate in the cellular response to osmotic swelling. These membrane proteins consist of heteromeric assemblies of LRRC8 subunits, whose compositions determine permeation properties. Although structures of the obligatory LRRC8A, also referred to as SWELL1, have previously defined the architecture of VRACs, the organization of heteromeric channels has remained elusive. Here we have addressed this question by the structural characterization of murine LRRC8A/C channels. Like LRRC8A, these proteins assemble as hexamers. Despite 12 possible arrangements, we find a predominant organization with an A:C ratio of two. In this assembly, four LRRC8A subunits cluster in their preferred conformation observed in homomers, as pairs of closely interacting proteins that stabilize a closed state of the channel. In contrast, the two interacting LRRC8C subunits show a larger flexibility, underlining their role in the destabilization of the tightly packed A subunits, thereby enhancing the activation properties of the protein.

Automated summary

Volume-regulated anion channels (VRACs) play a role in cellular response to osmotic swelling. These membrane proteins are composed of heteromeric assemblies of LRRC8 subunits, with compositions affecting permeation properties. In this study, the structure of murine LRRC8A/C channels was characterized. The assembly showed a predominant organization with an A:C ratio of two, with LRRC8A subunits stabilizing a closed state of the channel while LRRC8C subunits enhancing the activation properties.