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Polycystin 1 (often abbreviated to PC1) is a protein that in humans is encoded by the PKD1 gene [1][2]. Mutations of PKD1 are associated with most cases of autosomal dominant polycystic kidney disease (ADPKD), a severe hereditary disorder of the kidneys characterised by the development of renal cysts and severe kidney dysfunction [3].

Protein Structure and Function

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PC1 interacts with polycystin 2 via a cytoplasmic coiled-coil domain.

PC1 is a membrane-bound protein 4303 amino acids in length expressed largely upon the primary cilium, as well as apical membranes, adherens junctions, and desmosomes [4]. It possesses eleven transmembrane domains, a large extracellular N-terminal domain, and a short (~200 amino acid) cytoplasmic C-terminal domain [4][5]. This intracellular domain contains a coiled-coil domain through which PC1 interacts with polycystin 2 (PC2), a membrane-bound Ca2+-permeable ion channel.

PC1 acts as a mechano- and chemosensor for PC2, regulating the activity of the membrane-bound calcium ion channel. This interaction has also been implicated in regulating well-known cellular pathways, including Wnt signaling, cyclic adenosine monophosphate (cAMP), cystic fibrosis transmembrane conductance regulator (CFTR), and the general cell cycle. [16]

PC1 has been proposed to act as a G protein–coupled receptor [4][6]. The C-terminal domain may be cleaved in a number of different ways. In one instance, a ~35 kDa portion of the tail has been found to accumulate in the cell nucleus in response to decreased fluid flow in the mouse kidney [7]. In another instance, a 15 kDa fragment may be yielded, interacting with transcriptional activator and co-activator STAT6 and p100, or components of the canonical Wnt signaling pathway in an inhibitory manner [8][9].

Evidence suggests that PC1 mediates mechanosensation of fluid flow by the primary cilium in the renal epithelium and of mechanical deformation of articular cartilage [10].

Role in ADPKD

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ADPKD is one of the most common monogenic (caused by mutation by a single gene) disorders in humans. It causes multiple cysts to grow in the kidney. These cysts are filled with fluid and expand to the point of interfering with kidney function. In particular, it interferes with the function of nephrons, which are the microscopic and main functional units of the kidney. Each nephron acts as a filtration mechanism resulting in the production of urine. ADPKD interferes with this function by constricting against the nephrons, resulting in progressive kidney failure as well as other complications, such as high blood pressure and side and abdominal pain. PC1 is most prevalently expressed within the nephron segments, and mutations affecting the protein lead to hyper-growth of cysts. Mutations in PC1 underlie around 85% of the cases of ADPKD, with the other 15% being caused by PC2 mutations.

PC1 is expressed in a majority of nephron segments of the kidney. It is generally localized on the primary cilium of the apical surface of epithelial cells. Either an inactivation of the entire cilium structure or a loss-of-function (LOF) of PC1 are strongly linked to cyst formation characterized by ADPKD. The cysts are caused by reduced calcium signaling in the PC1-PC2 interaction (due to the LOF mutation), causing increased cAMP and protein kinase-A activity and therefore unmitigated cell proliferation and fluid secretion. However, studies have shown that simultaneous knockdown of both leads to slowed cyst progression compared to LOF of PC1 alone. A possible explanation is that PC1 regulates cilia-dependent signaling through a currently unknown pathway. This could be a possible target for treating and slowing down cyst growth in PKD1.

Gene

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Splice variants encoding different isoforms have been noted for PKD1. The gene is closely linked to six pseudogenes in a known duplicated region on chromosome 16p.[11]


References

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https://www.sciencedirect.com/science/article/pii/S1471491414000057. Accessed October 2018.

  1. ^ Hughes J, Ward CJ, Peral B, Aspinwall R, Clark K, San Millán JL, Gamble V, Harris PC (June 1995). "The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains". Nature Genetics. 10 (2): 151–60. doi:10.1038/ng0695-151. PMID 7663510.
  2. ^ "Polycystic kidney disease: the complete structure of the PKD1 gene and its protein. The International Polycystic Kidney Disease Consortium". Cell. 81 (2): 289–98. April 1995. doi:10.1016/0092-8674(95)90339-9. PMID 7736581.
  3. ^ Torres VE, Harris PC, Pirson Y (April 2007). "Autosomal dominant polycystic kidney disease". Lancet. 369 (9569): 1287–301. doi:10.1016/S0140-6736(07)60601-1. PMID 17434405.
  4. ^ a b c Zhou J (2009). "Polycystins and primary cilia: primers for cell cycle progression". Annual Review of Physiology. 71: 83–113. doi:10.1146/annurev.physiol.70.113006.100621. PMID 19572811.
  5. ^ Dalagiorgou G, Basdra EK, Papavassiliou AG (October 2010). "Polycystin-1: function as a mechanosensor". The International Journal of Biochemistry & Cell Biology. 42 (10): 1610–3. doi:10.1016/j.biocel.2010.06.017. PMID 20601082.
  6. ^ Trudel M, Yao Q, Qian F (January 2016). "The Role of G-Protein-Coupled Receptor Proteolysis Site Cleavage of Polycystin-1 in Renal Physiology and Polycystic Kidney Disease". Cells. 5 (1): 3. doi:10.3390/cells5010003. PMID 26805887.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  7. ^ Chauvet V, Tian X, Husson H, Grimm DH, Wang T, Hiesberger T, Hieseberger T, Igarashi P, Bennett AM, Ibraghimov-Beskrovnaya O, Somlo S, Caplan MJ (November 2004). "Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus". The Journal of Clinical Investigation. 114 (10): 1433–43. doi:10.1172/JCI21753. PMC 1052027. PMID 15545994.
  8. ^ Low SH, Vasanth S, Larson CH, Mukherjee S, Sharma N, Kinter MT, Kane ME, Obara T, Weimbs T (January 2006). "Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease". Developmental Cell. 10 (1): 57–69. doi:10.1016/j.devcel.2005.12.005. PMID 16399078.
  9. ^ Lal M, Song X, Pluznick JL, Di Giovanni V, Merrick DM, Rosenblum ND, Chauvet V, Gottardi CJ, Pei Y, Caplan MJ (October 2008). "Polycystin-1 C-terminal tail associates with beta-catenin and inhibits canonical Wnt signaling". Human Molecular Genetics. 17 (20): 3105–17. doi:10.1093/hmg/ddn208. PMC 2722884. PMID 18632682.
  10. ^ Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J (February 2003). "Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells". Nature Genetics. 33 (2): 129–37. doi:10.1038/ng1076. PMID 12514735.
  11. ^ "Entrez Gene: PKD1 polycystic kidney disease 1 (autosomal dominant)".
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