The heteromeric PC-1/PC-2 polycystin complex is activated by the PC-1 N-terminus
- University of California, San Francisco, United States
- University of Utah, United States
- University of Maryland School of Medicine, United States
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.
Data availability
Previously published data from PDB was used, available under the accession code 6A70.All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
National Institute of General Medical Sciences (R01GM130908)
- Markus Delling
Fritz Thyssen Stiftung
- Markus Delling
National Research Foundation of Korea (2019R1A6A3A03033302)
- Kodaji 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.
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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The heteromeric PC-1/PC-2 polycystin complex is activated by the PC-1 N-terminus
eLife 9:e60684.
https://doi.org/10.7554/eLife.60684
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