1. Cell Biology
  2. Structural Biology and Molecular Biophysics
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The heteromeric PC-1/PC-2 polycystin complex is activated by the PC-1 N-terminus

  1. Kotdaji Ha
  2. Mai Nobuhara
  3. Qinzhe Wang
  4. Rebecca V Walker
  5. Feng Qian
  6. Christoph Schartner
  7. Erhu Cao
  8. Markus Delling  Is a corresponding author
  1. University of California, San Francisco, United States
  2. University of Utah, United States
  3. University of Maryland School of Medicine, United States
Research Article
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Cite this article as: eLife 2020;9:e60684 doi: 10.7554/eLife.60684

Abstract

Mutations in the polycystin proteins, PC-1 and PC-2, result in autosomal dominant polycystic kidney disease (ADPKD) and ultimately renal failure. PC-1 and PC-2 enrich on primary cilia, where they are thought to form a heteromeric ion channel complex. However, a functional understanding of the putative PC-1/PC-2 polycystin complex is lacking due to technical hurdles in reliably measuring its activity. Here, we successfully reconstitute the PC-1/PC-2 complex in the plasma membrane of mammalian cells and show that it functions as an outwardly rectifying channel. Using both reconstituted and ciliary polycystin channels, we further show that a soluble fragment generated from the N-terminal extracellular domain of PC-1 functions as an intrinsic agonist that is necessary and sufficient for channel activation. We thus propose that autoproteolytic cleavage of the N-terminus of PC-1, a hotspot for ADPKD mutations, produces a soluble ligand in vivo. These findings establish a mechanistic framework for understanding the role of PC-1/PC-2 heteromers in ADPKD and suggest new therapeutic strategies that would expand upon the limited symptomatic treatments currently available for this progressive, terminal disease.

Article and author information

Author details

  1. Kotdaji Ha

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Mai Nobuhara

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Qinzhe Wang

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Rebecca V Walker

    Medicine, University of Maryland School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2473-4303
  5. Feng Qian

    Medicine, University of Maryland School of Medicine, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Christoph Schartner

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Erhu Cao

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Markus Delling

    Department of Physiology, University of California, San Francisco, San Francisco, United States
    For correspondence
    markus.delling@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9556-2097

Funding

National Institute of General Medical Sciences (R01GM130908)

  • Markus Delling

Fritz Thyssen Stiftung

  • Markus Delling

National Research Foundation of Korea (2019R1A6A3A03033302)

  • Kotdaji Ha

National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK111611)

  • Feng Qian

National Institute of Diabetes and Digestive and Kidney Diseases (U54DK126114)

  • Feng Qian

NIH Research Project Grant (DK110575)

  • Erhu Cao

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Polina V Lishko, University of California, Berkeley, United States

Publication history

  1. Received: July 2, 2020
  2. Accepted: November 6, 2020
  3. Accepted Manuscript published: November 9, 2020 (version 1)
  4. Accepted Manuscript updated: November 12, 2020 (version 2)

Copyright

? 2020, Ha et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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