title: Regulation of Polycystin-1 Function by Calmodulin Binding.
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.
authors: Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, United States of America.
authors: Nicholas
authors: N
authors: Doerr
authors: Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, United States of America.
authors: Yidi
authors: Y
authors: Wang
authors: Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, United States of America.
authors: Kevin R
authors: KR
authors: Kipp
authors: Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, United States of America.|Department of Nephrology, Qilu Hospital, Shandong University, Jinan, China.
authors: Guangyi
authors: G
authors: Liu
authors: Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, United States of America.
authors: Jesse J
authors: JJ
authors: Benza
authors: Department of Structural Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation.
authors: Vladimir
authors: V
authors: Pletnev
authors: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, United States of America.
authors: Tengis S
authors: TS
authors: Pavlov
authors: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, United States of America.
authors: Alexander
authors: A
authors: Staruschenko
authors: Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, United States of America.|University of California Irvine, Medical Campus, Orange, CA, United States of America.
authors: Ashraf M
authors: AM
authors: Mohieldin
authors: Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, United States of America.|University of California Irvine, Medical Campus, Orange, CA, United States of America.
authors: Maki
authors: M
authors: Takahashi
authors: Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, United States of America.|University of California Irvine, Medical Campus, Orange, CA, United States of America.
authors: Surya M
authors: SM
authors: Nauli
authors: Department of Molecular, Cellular, and Developmental Biology and Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA, United States of America.
authors: Thomas
authors: T
authors: Weimbs
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism*; D002923:Cilia; D003412:Cricetulus; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D009154:Mutation; D018995:Myosin Heavy Chains / Q000737:chemistry; D049897:Pectinidae; D016891:Polycystic Kidney, Autosomal Dominant / Q000378:metabolism*; D000072417:Protein Domains; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D002118:Calcium; D002147:Calmodulin; D018995:Myosin Heavy Chains; D050796:STAT3 Transcription Factor; D050396:TRPP Cation Channels; D018808:Transcription Factor AP-1