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dc.contributor.authorHa, K.
dc.contributor.authorNobuhara, M.
dc.contributor.authorWang, Q.
dc.contributor.authorWalker, R.V.
dc.contributor.authorQian, F.
dc.contributor.authorSchartner, C.
dc.contributor.authorCao, E.
dc.contributor.authorDelling, M.
dc.date.accessioned2021-02-08T20:13:35Z
dc.date.available2021-02-08T20:13:35Z
dc.date.issued2020-11-09
dc.identifier.urihttp://hdl.handle.net/10713/14587
dc.description.abstractMutations 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. Copyright Ha et al.en_US
dc.description.sponsorshipThis work was supported by National Institute of Health Grant R01GM130908 (MD), R01 DK111611 (FQ), Polycystic Kidney Disease Research Resource Consortium U54DK126114 (FQ), the Fritz Thyssen Foundation (MD), the National Research Foundation of Korea (NTF) grant funded by the Korean government (MSIT) (No.2019R1A6A3A03033302) (KH), PKD Foundation (236G19a) (FQ) and a fellowship grant (215F19a) (RW).en_US
dc.description.urihttps://doi.org/10.7554/eLife.60684en_US
dc.language.isoen_USen_US
dc.publishereLife Sciences Publications Ltden_US
dc.relation.ispartofeLife
dc.subject.meshPolycystic Kidney, Autosomal Dominant--geneticsen_US
dc.titleThe heteromeric pc-1/pc-2 polycystin complex is activated by the pc-1 n-terminusen_US
dc.typeArticleen_US
dc.identifier.doi10.7554/eLife.60684
dc.identifier.pmid33164752


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