Structure of a volume-regulated anion channel of the LRRC8 family [unknown]

D. Deneka, M. Sawicka, A.K.M. Lam, C. Paulino, R. Dutzler
2018 unpublished
Volume-regulated anion channels are activated in response to hypotonic stress. These channels are composed of closely related paralogues of the leucine-rich repeat-containing protein 8 (LRRC8) family that co-assemble to form hexameric complexes. Here, using cryo-electron microscopy and X-ray crystallography, we determine the structure of a homomeric channel of the obligatory subunit LRRC8A. This protein conducts ions and has properties in common with endogenous heteromeric channels. Its modular
more » ... annels. Its modular structure consists of a transmembrane pore domain followed by a cytoplasmic leucine-rich repeat domain. The transmembrane domain, which is structurally related to connexin proteins, is wide towards the cytoplasm but constricted on the outside by a structural unit that acts as a selectivity filter. An excess of basic residues in the filter and throughout the pore attracts anions by electrostatic interaction. Our work reveals the previously unknown architecture of volume-regulated anion channels and their mechanism of selective anion conduction. ; Dutzler, Raimund (2018). Structure of a volume-regulated anion channel of the LRRC8 family. Nature, 558(7709):254-259. * Both authors contributed equally to this work 2 Volume-regulated anion channels (VRACs) are activated in response to hypotonic stress. These channels are composed of closely related paralogs of the LRRC8 family, which coassemble to form hexameric complexes. Here we describe the structure of a homomeric channel of the obligatory subunit LRRC8A determined by cryo-electron microscopy and X-ray crystallography. This protein conducts ions and shares properties of endogenous heteromeric channels. Its modular structure consists of a transmembrane pore domain followed by a cytoplasmic leucine-rich repeat domain. The transmembrane domain, which is related to connexins, is wide towards the cytoplasm but constricted on the outside by a structural unit that acts as a selectivity filter. Anions are attracted by the positive electrostatics, in the filter and throughout the pore, conferred by an excess of basic residues. Our work reveals the previously unknown architecture of VRACs and their mechanism of selective anion conduction.
doi:10.2210/pdb6fnw/pdb fatcat:sahz5zmsuvcg7kcqp6be6kpxha