Regulation of Polycystin-1 Function by Calmodulin Binding

Authors

Nicholas Doerr, University of California, Santa Barbara
Yidi Wang, University of California, Santa Barbara
Kevin R. Kipp, University of California, Santa Barbara
Guangyi Liu, University of California, Santa Barbara
Jesse J. Benza, University of California, Santa Barbara
Vladimir Pletnev, Russian Academy of Sciences
Tengis S. Pavlov, Medical College of Wisconsin
Alexander Staruschenko, Medical College of Wisconsin
Ashraf M. Mohieldin, Chapman University
Maki Takahashi, Chapman University
Surya M. Nauli, Chapman UniversityFollow
Thomas Weimbs, University of California, Santa Barbara

Document Type

Article

Publication Date

8-25-2016

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 CaMbinding 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.

Comments

This article was originally published in PLoS ONE, volume 11, issue 8, in 2016. DOI: 10.1371/journal.pone.0161525

Recommended Citation

Doerr N, Wang Y, Kipp KR, Liu G, Benza JJ, Pletnev V, et al. (2016) Regulation of Polycystin-1 Function by Calmodulin Binding. PLoS ONE 11(8): e0161525. doi:10.1371/journal.pone.0161525

Copyright

The authors

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.