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Regulation of Polycystin-1 Function by Calmodulin Binding.

By Nicholas Doerr, Yidi Wang, Kevin R Kipp, Guangyi Liu, Jesse J Benza, Vladimir Pletnev, Tengis S Pavlov, Alexander Staruschenko, Ashraf M Mohieldin, Maki Takahashi, Surya M Nauli and Thomas Weimbs

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common genetic disease that leads to progressive renal cyst growth and loss of renal function, and is caused by mutations in the genes encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively. The PC1/PC2 complex localizes to primary cilia and can act as a flow-dependent calcium channel in addition to numerous other signaling functions. The exact functions of the polycystins, their regulation and the purpose of the PC1/PC2 channel are still poorly understood. PC1 is an integral membrane protein with a large extracytoplasmic N-terminal domain and a short, ~200 amino acid C-terminal cytoplasmic tail. Most proteins that interact with PC1 have been found to bind via the cytoplasmic tail. Here we report that the PC1 tail has homology to the regulatory domain of myosin heavy chain including a conserved calmodulin-binding motif. This motif binds to CaM in a calcium-dependent manner. Disruption of the CaM-binding motif in PC1 does not affect PC2 binding, cilia targeting, or signaling via heterotrimeric G-proteins or STAT3. However, disruption of CaM binding inhibits the PC1/PC2 calcium channel activity and the flow-dependent calcium response in kidney epithelial cells. Furthermore, expression of CaM-binding mutant PC1 disrupts cellular energy metabolism. These results suggest that critical functions of PC1 are regulated by its ability to sense cytosolic calcium levels via binding to CaM

Topics: Kidney, CHO Cells, Cilia, Cytoplasm, Cytosol, Animals, Dogs, Humans, Cricetulus, Mice, Polycystic Kidney, Autosomal Dominant, Calcium, Calmodulin, Myosin Heavy Chains, Transcription Factor AP-1, Signal Transduction, Binding Sites, Amino Acid Motifs, Mutation, Pectinidae, TRPP Cation Channels, STAT3 Transcription Factor, HEK293 Cells, Madin Darby Canine Kidney Cells, Protein Domains, Polycystic Kidney, Autosomal Dominant, General Science & Technology
Publisher: eScholarship, University of California
Year: 2016
OAI identifier: oai:escholarship.org/ark:/13030/qt7pn0w1cg

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