Polycystin 1 Explained

Polycystin 1 (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, a severe hereditary disorder of the kidneys characterised by the development of renal cysts and severe kidney dysfunction.^[3]

Protein structure and function

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 has 11 transmembrane domains, a large extracellular N-terminal domain, and a short (about 200 amino acid) cytoplasmic C-terminal domain.^[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 has been proposed to act as a G protein–coupled receptor.^[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]}

The structure of the human PKD1-PKD2 complex has been solved by cryo-electron microscopy, which showed a 1:3 ratio of PKD1 and PKD2 in the structure. PKD1 consists of a voltage-gated ion channel fold that interacts with PKD2.^[10]

PC1 mediates mechanosensation of fluid flow by the primary cilium in the renal epithelium and of mechanical deformation of articular cartilage.^[11]

Gene

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.^[12]

External links

• GeneReviews/NIH/NCBI/UW entry on Polycystic Kidney Disease, Autosomal Dominant

Notes and References

1. Hughes J, Ward CJ, Peral B, Aspinwall R, Clark K, San Millán JL, Gamble V, Harris PC . The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains . Nature Genetics . 10 . 2 . 151–60 . June 1995 . 7663510 . 10.1038/ng0695-151 . 20636101 .
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 . 7736581 . 10.1016/0092-8674(95)90339-9 . 11114706 . free .
3. Torres VE, Harris PC, Pirson Y . Autosomal dominant polycystic kidney disease . Lancet . 369 . 9569 . 1287–301 . April 2007 . 17434405 . 10.1016/S0140-6736(07)60601-1 . 1700992 .
4. Zhou J . Polycystins and primary cilia: primers for cell cycle progression . Annual Review of Physiology . 71 . 83–113 . 2009 . 19572811 . 10.1146/annurev.physiol.70.113006.100621 .
5. Dalagiorgou G, Basdra EK, Papavassiliou AG . Polycystin-1: function as a mechanosensor . The International Journal of Biochemistry & Cell Biology . 42 . 10 . 1610–3 . October 2010 . 20601082 . 10.1016/j.biocel.2010.06.017 .
6. Trudel M, Yao Q, Qian F . The Role of G-Protein-Coupled Receptor Proteolysis Site Cleavage of Polycystin-1 in Renal Physiology and Polycystic Kidney Disease . Cells . 5 . 1 . 3 . January 2016 . 26805887 . 4810088 . 10.3390/cells5010003 . free .
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 . Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus . The Journal of Clinical Investigation . 114 . 10 . 1433–43 . November 2004 . 15545994 . 10.1172/JCI21753 . 1052027 .
8. Low SH, Vasanth S, Larson CH, Mukherjee S, Sharma N, Kinter MT, Kane ME, Obara T, Weimbs T . 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 . January 2006 . 16399078 . 10.1016/j.devcel.2005.12.005 . free .
9. Lal M, Song X, Pluznick JL, Di Giovanni V, Merrick DM, Rosenblum ND, Chauvet V, Gottardi CJ, Pei Y, Caplan MJ . Polycystin-1 C-terminal tail associates with beta-catenin and inhibits canonical Wnt signaling . Human Molecular Genetics . 17 . 20 . 3105–17 . October 2008 . 18632682 . 2722884 . 10.1093/hmg/ddn208 .
10. Shi. Yigong. Mei. Changlin. Zhou. Qiang. Wang. Tingliang. Yu. Shengqiang. Lei. Jianlin. Ge. Xiaofei. Hu. Feizhuo. Su. Qiang. 2018-09-07. Structure of the human PKD1-PKD2 complex. Science. en. 361. 6406. eaat9819. 10.1126/science.aat9819. 0036-8075. 30093605. free.
11. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J . Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells . En . Nature Genetics . 33 . 2 . 129–37 . February 2003 . 12514735 . 10.1038/ng1076 . 23149223 .
12. Web site: Entrez Gene: PKD1 polycystic kidney disease 1 (autosomal dominant).