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

Author

Listed:
  • Dawid Deneka

    (University of Zurich)

  • Marta Sawicka

    (University of Zurich)

  • Andy K. M. Lam

    (University of Zurich)

  • Cristina Paulino

    (University of Zurich
    Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen)

  • Raimund Dutzler

    (University of Zurich)

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.

Suggested Citation

  • Dawid Deneka & Marta Sawicka & Andy K. M. Lam & Cristina Paulino & Raimund Dutzler, 2018. "Structure of a volume-regulated anion channel of the LRRC8 family," Nature, Nature, vol. 558(7709), pages 254-259, June.
    • Handle: RePEc:nat:nature:v:558:y:2018:i:7709:d:10.1038_s41586-018-0134-y
    DOI: 10.1038/s41586-018-0134-y
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    Cited by:

    1. Yuman Wang & Zaiqiao Sun & Jieming Ping & Jianlong Tang & Boxiao He & Teding Chang & Qian Zhou & Shijie Yuan & Zhaohui Tang & Xin Li & Yan Lu & Ran He & Ximiao He & Zheng Liu & Lei Yin & Ning Wu, 2023. "Cell volume controlled by LRRC8A-formed volume-regulated anion channels fine-tunes T cell activation and function," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Nazia Hussain & Ashish Apotikar & Shabareesh Pidathala & Sourajit Mukherjee & Ananth Prasad Burada & Sujit Kumar Sikdar & Kutti R. Vinothkumar & Aravind Penmatsa, 2024. "Cryo-EM structures of pannexin 1 and 3 reveal differences among pannexin isoforms," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Zhihui He & Yonghui Zhao & Michael J. Rau & James A. J. Fitzpatrick & Rajan Sah & Hongzhen Hu & Peng Yuan, 2023. "Structural and functional analysis of human pannexin 2 channel," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    4. Hang Zhang & Shiyu Wang & Zhenzhen Zhang & Mengzhuo Hou & Chunyu Du & Zhenye Zhao & Horst Vogel & Zhifang Li & Kaige Yan & Xiaokang Zhang & Jianping Lu & Yujie Liang & Shuguang Yuan & Daping Wang & Hu, 2023. "Cryo-EM structure of human heptameric pannexin 2 channel," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    5. Susheel K. Gunasekar & Litao Xie & Ashutosh Kumar & Juan Hong & Pratik R. Chheda & Chen Kang & David M. Kern & Chau My-Ta & Joshua Maurer & John Heebink & Eva E. Gerber & Wojciech J. Grzesik & Macaula, 2022. "Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes," Nature Communications, Nature, vol. 13(1), pages 1-25, December.

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