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Structure and insights into the function of a Ca2+-activated Cl− channel

Author

Listed:
  • Veronica Kane Dickson

    (Structural Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA)

  • Leanne Pedi

    (Structural Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA)

  • Stephen B. Long

    (Structural Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA)

Abstract

Bestrophin calcium-activated chloride channels (CaCCs) regulate the flow of chloride and other monovalent anions across cellular membranes in response to intracellular calcium (Ca2+) levels. Mutations in bestrophin 1 (BEST1) cause certain eye diseases. Here we present X-ray structures of chicken BEST1–Fab complexes, at 2.85 Å resolution, with permeant anions and Ca2+. Representing, to our knowledge, the first structure of a CaCC, the eukaryotic BEST1 channel, which recapitulates CaCC function in liposomes, is formed from a pentameric assembly of subunits. Ca2+ binds to the channel’s large cytosolic region. A single ion pore, approximately 95 Å in length, is located along the central axis and contains at least 15 binding sites for anions. A hydrophobic neck within the pore probably forms the gate. Phenylalanine residues within it may coordinate permeating anions via anion–π interactions. Conformational changes observed near the ‘Ca2+ clasp’ hint at the mechanism of Ca2+-dependent gating. Disease-causing mutations are prevalent within the gating apparatus.

Suggested Citation

  • Veronica Kane Dickson & Leanne Pedi & Stephen B. Long, 2014. "Structure and insights into the function of a Ca2+-activated Cl− channel," Nature, Nature, vol. 516(7530), pages 213-218, December.
    • Handle: RePEc:nat:nature:v:516:y:2014:i:7530:d:10.1038_nature13913
    DOI: 10.1038/nature13913
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    Cited by:

    1. Tatsuya Hagino & Takafumi Kato & Go Kasuya & Kan Kobayashi & Tsukasa Kusakizako & Shin Hamamoto & Tomoaki Sobajima & Yuichiro Fujiwara & Keitaro Yamashita & Hisashi Kawasaki & Andrés D. Maturana & Tom, 2022. "Cryo-EM structures of thylakoid-located voltage-dependent chloride channel VCCN1," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Aaron P. Owji & Jiali Wang & Alec Kittredge & Zada Clark & Yu Zhang & Wayne A. Hendrickson & Tingting Yang, 2022. "Structures and gating mechanisms of human bestrophin anion channels," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. 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.
    4. Jiali Wang & Aaron P. Owji & Alec Kittredge & Zada Clark & Yu Zhang & Tingting Yang, 2024. "GAD65 tunes the functions of Best1 as a GABA receptor and a neurotransmitter conducting channel," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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