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.
Highlights
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common, life-threatening genetic disease with an estimated prevalence between 1:400–1:1000 live births
In this work we find that the membrane-proximal region of the PC1 cytoplasmic tail has predicted structural homology to the regulatory domain of myosin heavy chains that is known to interact with calmodulin (CaM) or the CaM-related regulatory myosin light chains
Pairwise alignments led to the identification of a portion of the PC1 tail with significant homology to the regulatory domain of scallop myosin (Fig 1A)
Summary
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common, life-threatening genetic disease with an estimated prevalence between 1:400–1:1000 live births. PC1 and PC2 localize to the primary cilium and bind each other through their C-terminal coiled-coil domains suggesting that they function together as a complex This interaction is required for calcium entry in response to apical fluid flow and bending of primary cilia [5]. The structural model of this region includes conserved, predicted CaM binding sites, the conserved G-protein activation domain and the nuclear localization signal of the PC1 tail. Mutation of the main CaM binding site disrupts the CaM interaction and leads to impaired Ca2+ channel activity of the PC1/PC2 complex, and loss of flow/cilia-mediated intracellular Ca2+ signaling. Disruption of the CaM binding site leads to altered PC1-dependent regulation of cellular metabolism These results suggest that Ca2+/CaM plays an important role in regulating the function of the PC1/PC2 complex
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