Polycystins and partners: proposed role in mechanosensitivity

Abstract

Mutations of the two polycystins, PC1 and PC2, lead to polycystic kidney disease. Polycystins are able to form complexes with numerous families of proteins that have been suggested to participate in mechanical sensing. The proposed role of polycystins and their partners in the kidney primary cilium is to sense urine flow. A role for polycystins in mechanosensing has also been shown in other cell types such as vascular smooth muscle cells and cardiac myocytes. At the plasma membrane, polycystins interact with diverse ion channels of the TRP family and with stretch-activated channels (Piezos, TREKs). The actin cytoskeleton and its interacting proteins, such as filamin A, have been shown to be essential for these interactions. Numerous proteins involved in cell-cell and cell-extracellular matrix junctions interact with PC1 and/or PC2. These multimeric protein complexes are important for cell structure integrity, the transmission of force, as well as for mechanosensing and mechanotransduction. A group of polycystin partners are also involved in subcellular trafficking mechanisms. Finally, PC1 and especially PC2 interact with elements of the endoplasmic reticulum and are essential components of calcium homeostasis.In conclusion, we propose that both PC1 and PC2 act as conductors to tune the overall cellular mechanosensitivity.

Crystal Structure of a Two-domain Fragment of Hepatocyte Growth Factor Activator Inhibitor-1

“…Polycystin-1 is a glycoprotein consisting of a long N-terminal extracellular region, multiple transmembrane domains, and a cytoplasmic tail. The N-terminal extracellular region contains 16 PKD domains thought to play a part in the mechanical stress-sensing function of polycystin-1 (48). Several naturally occurring mutations within polycystin-1 result in autosomal dominant polycystic kidney disease (49).…”

Mating behavior, male sensory cilia, and polycystins in Caenorhabditis elegans

“…Polycystin 1 proteins are characterized by a long adhesive N-terminal extracellular domain containing PKD domain repeats, 11 transmembrane (TM) domains, a GAIN domain including a GPCR proteolysis site (GPS), an intracellular PLAT ( p olycystin/ l ipoxygenase/ α - t oxin) domain between TM1 and TM2, and a coiled-coil region in the carboxy-terminus (thought to interact directly with polycystin 2), that are either predicted or experimentally confirmed (Fig. 2; [32-36]). The region spanning the last six transmembrane domains is homologous with polycystin 2 [37].…”

Chronic heart failure: Ca 2+ , catabolism, and catastrophic cell death

“…By forming a multiprotein ion channel complex with polycystin-1 (PC1), PC2 participates in the function of primary cilia. There, these proteins respond to a variety of extracellular cues, transducing them into changes in intracellular Ca 2+ [232]. Changes in conformational shape triggered by shear stress on primary cilia lead to activation of the PC1/PC2 complex and consequent changes in intracellular Ca 2+ levels [232].…”

“…There, these proteins respond to a variety of extracellular cues, transducing them into changes in intracellular Ca 2+ [232]. Changes in conformational shape triggered by shear stress on primary cilia lead to activation of the PC1/PC2 complex and consequent changes in intracellular Ca 2+ levels [232]. Now, very recent evidence suggests that PC2-dependent changes in Ca 2+ may be important in driving autophagosome formation (unpublished observations).…”