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Hydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels

Author

Listed:
  • Wang Zheng

    (Hubei University of Technology
    University of Alberta)

  • Xiaoyong Yang

    (University of Utah School of Medicine)

  • Ruikun Hu

    (Tongji University)

  • Ruiqi Cai

    (University of Alberta)

  • Laura Hofmann

    (Universität des Saarlandes)

  • Zhifei Wang

    (St. John’s University)

  • Qiaolin Hu

    (University of Alberta)

  • Xiong Liu

    (University of Alberta)

  • David Bulkley

    (University of California, San Francisco)

  • Yong Yu

    (St. John’s University)

  • Jingfeng Tang

    (Hubei University of Technology)

  • Veit Flockerzi

    (Universität des Saarlandes)

  • Ying Cao

    (Tongji University)

  • Erhu Cao

    (University of Utah School of Medicine)

  • Xing-Zhen Chen

    (Hubei University of Technology
    University of Alberta)

Abstract

PKD2 and PKD1 genes are mutated in human autosomal dominant polycystic kidney disease. PKD2 can form either a homomeric cation channel or a heteromeric complex with the PKD1 receptor, presumed to respond to ligand(s) and/or mechanical stimuli. Here, we identify a two-residue hydrophobic gate in PKD2L1, and a single-residue hydrophobic gate in PKD2. We find that a PKD2 gain-of-function gate mutant effectively rescues PKD2 knockdown-induced phenotypes in embryonic zebrafish. The structure of a PKD2 activating mutant F604P by cryo-electron microscopy reveals a π- to α-helix transition within the pore-lining helix S6 that leads to repositioning of the gate residue and channel activation. Overall the results identify hydrophobic gates and a gating mechanism of PKD2 and PKD2L1.

Suggested Citation

  • Wang Zheng & Xiaoyong Yang & Ruikun Hu & Ruiqi Cai & Laura Hofmann & Zhifei Wang & Qiaolin Hu & Xiong Liu & David Bulkley & Yong Yu & Jingfeng Tang & Veit Flockerzi & Ying Cao & Erhu Cao & Xing-Zhen C, 2018. "Hydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04586-x
    DOI: 10.1038/s41467-018-04586-x
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    Cited by:

    1. Kodaji Ha & Nadine Mundt-Machado & Paola Bisignano & Aide Pinedo & David R. Raleigh & Gabriel Loeb & Jeremy F. Reiter & Erhu Cao & Markus Delling, 2024. "Cilia-enriched oxysterol 7β,27-DHC is required for polycystin ion channel activation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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