The heteromeric PC-1/PC-2 polycystin complex is activated by the PC-1 N-terminus
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 putati...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/60684 |
| _version_ | 1811253151410421760 |
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| author | Kotdaji Ha Mai Nobuhara Qinzhe Wang Rebecca V Walker Feng Qian Christoph Schartner Erhu Cao Markus Delling |
| author_facet | Kotdaji Ha Mai Nobuhara Qinzhe Wang Rebecca V Walker Feng Qian Christoph Schartner Erhu Cao Markus Delling |
| author_sort | Kotdaji Ha |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T16:46:18Z |
| format | Article |
| id | doaj.art-aedf6706a94d481e92e4965e72048760 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:46:18Z |
| publishDate | 2020-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-aedf6706a94d481e92e4965e720487602022-12-22T03:24:35ZengeLife Sciences Publications LtdeLife2050-084X2020-11-01910.7554/eLife.60684The heteromeric PC-1/PC-2 polycystin complex is activated by the PC-1 N-terminusKotdaji Ha0Mai Nobuhara1Qinzhe Wang2Rebecca V Walker3https://orcid.org/0000-0002-2473-4303Feng Qian4Christoph Schartner5Erhu Cao6Markus Delling7https://orcid.org/0000-0001-9556-2097Department of Physiology, University of California, San Francisco, San Francisco, United StatesDepartment of Physiology, University of California, San Francisco, San Francisco, United StatesDepartment of Biochemistry, University of Utah School of Medicine, Salt Lake City, United StatesDivision of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, United StatesDivision of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, United StatesDepartment of Physiology, University of California, San Francisco, San Francisco, United StatesDepartment of Biochemistry, University of Utah School of Medicine, Salt Lake City, United StatesDepartment of Physiology, University of California, San Francisco, San Francisco, United StatesMutations 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.https://elifesciences.org/articles/60684primary ciliapolycystin channelsADPKDkidney |
| spellingShingle | Kotdaji Ha Mai Nobuhara Qinzhe Wang Rebecca V Walker Feng Qian Christoph Schartner Erhu Cao Markus Delling The heteromeric PC-1/PC-2 polycystin complex is activated by the PC-1 N-terminus eLife primary cilia polycystin channels ADPKD kidney |
| title | The heteromeric PC-1/PC-2 polycystin complex is activated by the PC-1 N-terminus |
| title_full | The heteromeric PC-1/PC-2 polycystin complex is activated by the PC-1 N-terminus |
| title_fullStr | The heteromeric PC-1/PC-2 polycystin complex is activated by the PC-1 N-terminus |
| title_full_unstemmed | The heteromeric PC-1/PC-2 polycystin complex is activated by the PC-1 N-terminus |
| title_short | The heteromeric PC-1/PC-2 polycystin complex is activated by the PC-1 N-terminus |
| title_sort | heteromeric pc 1 pc 2 polycystin complex is activated by the pc 1 n terminus |
| topic | primary cilia polycystin channels ADPKD kidney |
| url | https://elifesciences.org/articles/60684 |
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