RT Journal Article
SR Electronic
T1 Structure of a volume-regulated heteromeric LRRC8A/C channel
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.08.03.502623
DO 10.1101/2022.08.03.502623
A1 Sonja Rutz
A1 Dawid Deneka
A1 Antje Dittmann
A1 Marta Sawicka
A1 Raimund Dutzler
YR 2022
UL http://biorxiv.org/content/early/2022/08/03/2022.08.03.502623.abstract
AB Volume-regulated anion channels participate in the cellular response to osmotic swelling. These heteromeric membrane proteins consist of LRRC8 family members, where the subunit composition determines permeation properties. Although structures of the obligatory LRRC8A subunit have previously defined the architecture of VRACs, the organization of heteromeric channels has remained elusive. Here we have closed this gap by the structural characterization of channels consisting of LRRC8A and LRRC8C. Like homomeric LRRC8A, these proteins assemble as hexamers. Despite twelve possible arrangements, we find a single predominant organization with an A:C ratio of two. In this assembly, four LRRCA 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.Competing Interest StatementThe authors have declared no competing interest.