Allosteric modulation of LRRC8 channels by targeting their cytoplasmic domains

• DOI: 10.1038/s41467-021-25742-w
• Publication Date: 2021-09-14T10:03:16Z
• Authors: Dawid Deneka; Sonja Rutz; Cedric A. J. Hutter; Markus A. Seeger; Marta Sawicka; Raimund Dutzler
• Keywords: Homomeric; Leucine-rich repeat

Members of the LRRC8 family form heteromeric assemblies, which function as volume-regulated anion channels. These modular proteins consist a transmembrane pore and cytoplasmic leucine-rich repeat (LRR) domains. Despite their known molecular architecture, mechanism activation role LRR domains in this process has remained elusive. Here we address question by generating synthetic nanobodies, termed sybodies, target domain obligatory subunit LRRC8A. We use these binders to investigate interaction with homomeric LRRC8A channels cryo-electron microscopy consequent effect on channel electrophysiology. The five identified sybodies either inhibit or enhance activity binding distinct epitopes domain, thereby altering conformations. In combination, our work provides set specific modulators reveals regulators allosteric mechanisms.