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Structure of a volume-regulated anion channel of the LRRC8 family

Dawid Deneka, Marta Sawicka, Andy K. M. Lam, Cristina Paulino and Raimund Dutzler ()
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Dawid Deneka: University of Zurich
Marta Sawicka: University of Zurich
Andy K. M. Lam: University of Zurich
Cristina Paulino: University of Zurich
Raimund Dutzler: University of Zurich

Nature, 2018, vol. 558, issue 7709, 254-259

Abstract: Abstract 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 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.

Date: 2018
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DOI: 10.1038/s41586-018-0134-y

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