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Regulation of Polycystin-1 Function by Calmodulin Binding

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...

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Autores principales: Doerr, Nicholas, Wang, Yidi, Kipp, Kevin R., Liu, Guangyi, Benza, Jesse J., Pletnev, Vladimir, Pavlov, Tengis S., Staruschenko, Alexander, Mohieldin, Ashraf M., Takahashi, Maki, Nauli, Surya M., Weimbs, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999191/
https://www.ncbi.nlm.nih.gov/pubmed/27560828
http://dx.doi.org/10.1371/journal.pone.0161525
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author Doerr, Nicholas
Wang, Yidi
Kipp, Kevin R.
Liu, Guangyi
Benza, Jesse J.
Pletnev, Vladimir
Pavlov, Tengis S.
Staruschenko, Alexander
Mohieldin, Ashraf M.
Takahashi, Maki
Nauli, Surya M.
Weimbs, Thomas
author_facet Doerr, Nicholas
Wang, Yidi
Kipp, Kevin R.
Liu, Guangyi
Benza, Jesse J.
Pletnev, Vladimir
Pavlov, Tengis S.
Staruschenko, Alexander
Mohieldin, Ashraf M.
Takahashi, Maki
Nauli, Surya M.
Weimbs, Thomas
author_sort Doerr, Nicholas
collection PubMed
description 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.
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spelling pubmed-49991912016-09-12 Regulation of Polycystin-1 Function by Calmodulin Binding Doerr, Nicholas Wang, Yidi Kipp, Kevin R. Liu, Guangyi Benza, Jesse J. Pletnev, Vladimir Pavlov, Tengis S. Staruschenko, Alexander Mohieldin, Ashraf M. Takahashi, Maki Nauli, Surya M. Weimbs, Thomas PLoS One Research Article 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. Public Library of Science 2016-08-25 /pmc/articles/PMC4999191/ /pubmed/27560828 http://dx.doi.org/10.1371/journal.pone.0161525 Text en © 2016 Doerr et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Doerr, Nicholas
Wang, Yidi
Kipp, Kevin R.
Liu, Guangyi
Benza, Jesse J.
Pletnev, Vladimir
Pavlov, Tengis S.
Staruschenko, Alexander
Mohieldin, Ashraf M.
Takahashi, Maki
Nauli, Surya M.
Weimbs, Thomas
Regulation of Polycystin-1 Function by Calmodulin Binding
title Regulation of Polycystin-1 Function by Calmodulin Binding
title_full Regulation of Polycystin-1 Function by Calmodulin Binding
title_fullStr Regulation of Polycystin-1 Function by Calmodulin Binding
title_full_unstemmed Regulation of Polycystin-1 Function by Calmodulin Binding
title_short Regulation of Polycystin-1 Function by Calmodulin Binding
title_sort regulation of polycystin-1 function by calmodulin binding
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999191/
https://www.ncbi.nlm.nih.gov/pubmed/27560828
http://dx.doi.org/10.1371/journal.pone.0161525
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