title: The Polycystin-1, Lipoxygenase, and α-Toxin Domain Regulates Polycystin-1 Trafficking.
abstract: Mutations in polycystin-1 (PC1) give rise to autosomal dominant polycystic kidney disease, an important and common cause of kidney failure. Despite its medical importance, the function of PC1 remains poorly understood. Here, we investigated the role of the intracellular polycystin-1, lipoxygenase, and α-toxin (PLAT) signature domain of PC1 using nuclear magnetic resonance, biochemical, cellular, and in vivo functional approaches. We found that the PLAT domain targets PC1 to the plasma membrane in polarized epithelial cells by a mechanism involving the selective binding of the PLAT domain to phosphatidylserine and L-α-phosphatidylinositol-4-phosphate (PI4P) enriched in the plasma membrane. This process is regulated by protein kinase A phosphorylation of the PLAT domain, which reduces PI4P binding and recruits β-arrestins and the clathrin adaptor AP2 to trigger PC1 internalization. Our results reveal a physiological role for the PC1-PLAT domain in renal epithelial cells and suggest that phosphorylation-dependent internalization of PC1 is closely linked to its function in renal development and homeostasis.
authors: Kidney Genetics Group, Academic Nephrology Unit, University of Sheffield Medical School, Sheffield, United Kingdom; Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, United Kingdom;
authors: Yaoxian
authors: Y
authors: Xu
authors: Kidney Genetics Group, Academic Nephrology Unit, University of Sheffield Medical School, Sheffield, United Kingdom;
authors: Andrew J
authors: AJ
authors: Streets
authors: Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, United Kingdom;
authors: Andrea M
authors: AM
authors: Hounslow
authors: Department of Cellular and Molecular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio; and.
authors: Uyen
authors: U
authors: Tran
authors: Laboratory of GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors: Frederic
authors: F
authors: Jean-Alphonse
authors: Kidney Genetics Group, Academic Nephrology Unit, University of Sheffield Medical School, Sheffield, United Kingdom;
authors: Andrew J
authors: AJ
authors: Needham
authors: Laboratory of GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors: Jean-Pierre
authors: JP
authors: Vilardaga
authors: Department of Cellular and Molecular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio; and.
authors: Oliver
authors: O
authors: Wessely
authors: Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, United Kingdom;
authors: Michael P
authors: MP
authors: Williamson
authors: Kidney Genetics Group, Academic Nephrology Unit, University of Sheffield Medical School, Sheffield, United Kingdom; a.ong@sheffield.ac.uk.
authors: Albert C M
authors: AC
authors: Ong
mesh_terms: D006801:Humans; D008084:Lipoxygenase / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D017434:Protein Structure, Tertiary; D050396:TRPP Cation Channels / Q000235:genetics / Q000502:physiology*
chemical_list: D008084:Lipoxygenase; D050396:TRPP Cation Channels
keywords: autosomal dominant polycystic kidney disease; genetics and development; polycystic kidney disease