Polycystin 1

Last updated
PKD1
Protein PKD1 PDB 1b4r.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PKD1 , PBP, Pc-1, TRPP1, polycystin 1, transient receptor potential channel interacting, PC1
External IDs OMIM: 601313 MGI: 97603 HomoloGene: 250 GeneCards: PKD1
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000296
NM_001009944

NM_013630

RefSeq (protein)

NP_000287
NP_001009944

NP_038658

Location (UCSC) Chr 16: 2.09 – 2.14 Mb Chr 17: 24.55 – 24.6 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Polycystin 1 (PC1) is a protein that in humans is encoded by the PKD1 gene. [5] [6] 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. [7]

Contents

Protein structure and function

PC1 interacts with polycystin 2 by a cytoplasmic coiled-coil domain. PKD1PKD2 en.png
PC1 interacts with polycystin 2 by 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. [8] It has 11 transmembrane domains, a large extracellular N-terminal domain, and a short (about 200 amino acid) cytoplasmic C-terminal domain. [8] [9] 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. [8] [10] 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. [11] 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. [12] [13]

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. [14]

PC1 mediates mechanosensation of fluid flow by the primary cilium in the renal epithelium and of mechanical deformation of articular cartilage. [15]

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. [16]

Related Research Articles

<span class="mw-page-title-main">Autosomal dominant polycystic kidney disease</span> Medical condition

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common, life-threatening inherited human disorders and the most common hereditary kidney disease. It is associated with large interfamilial and intrafamilial variability, which can be explained to a large extent by its genetic heterogeneity and modifier genes. It is also the most common of the inherited cystic kidney diseases — a group of disorders with related but distinct pathogenesis, characterized by the development of renal cysts and various extrarenal manifestations, which in case of ADPKD include cysts in other organs, such as the liver, seminal vesicles, pancreas, and arachnoid membrane, as well as other abnormalities, such as intracranial aneurysms and dolichoectasias, aortic root dilatation and aneurysms, mitral valve prolapse, and abdominal wall hernias. Over 50% of patients with ADPKD eventually develop end stage kidney disease and require dialysis or kidney transplantation. ADPKD is estimated to affect at least one in every 1000 individuals worldwide, making this disease the most common inherited kidney disorder with a diagnosed prevalence of 1:2000 and incidence of 1:3000-1:8000 in a global scale.

<span class="mw-page-title-main">Cystic kidney disease</span> Medical condition

Cystic kidney disease refers to a wide range of hereditary, developmental, and acquired conditions and with the inclusion of neoplasms with cystic changes, over 40 classifications and subtypes have been identified. Depending on the disease classification, the presentation may be at birth, or much later into adult life. Cystic disease may involve one or both kidneys and may, or may not, occur in the presence of other anomalies. A higher incidence is found in males and prevalence increases with age. Renal cysts have been reported in more than 50% of patients over the age of 50. Typically, cysts grow up to 2.88 mm annually and may cause related pain and/or hemorrhage.

<span class="mw-page-title-main">Uromodulin</span> Mammalian protein found in Homo sapiens

Uromodulin (UMOD), also known as Tamm–Horsfall protein (THP), is a zona pellucida-like domain-containing glycoprotein that in humans is encoded by the UMOD gene. Uromodulin is the most abundant protein excreted in ordinary urine.

<span class="mw-page-title-main">Fibrocystin</span>

Fibrocystin is a large, receptor-like protein that is thought to be involved in the tubulogenesis and/or maintenance of duct-lumen architecture of epithelium. FPC associates with the primary cilia of epithelial cells and co-localizes with the Pkd2 gene product polycystin-2 (PC2), suggesting that these two proteins may function in a common molecular pathway.

TRPP is a family of transient receptor potential ion channels which when mutated can cause polycystic kidney disease.

<span class="mw-page-title-main">Collagen, type IV, alpha 3</span> Protein found in humans

Collagen alpha-3(IV) chain is a protein that in humans is encoded by the COL4A3 gene.

<span class="mw-page-title-main">Polycystin 2</span> Protein and coding gene in humans

Polycystin-2(PC2) is a protein that in humans is encoded by the PKD2 gene.

<span class="mw-page-title-main">PRKCSH</span> Protein-coding gene in the species Homo sapiens

Glucosidase 2 subunit beta is an enzyme that in humans is encoded by the PRKCSH gene.

<span class="mw-page-title-main">PKD2L1</span> Protein-coding gene in the species Homo sapiens

Polycystic kidney disease 2-like 1 protein also known as transient receptor potential polycystic 2 is a protein that in humans is encoded by the PKD2L1 gene.

<span class="mw-page-title-main">HAX1</span> Mammalian protein found in Homo sapiens

HCLS1-associated protein X-1 is a protein that in humans is encoded by the HAX1 gene.

<span class="mw-page-title-main">Ciliopathy</span> Genetic disease resulting in abnormal formation or function of cilia

A ciliopathy is any genetic disorder that affects the cellular cilia or the cilia anchoring structures, the basal bodies, or ciliary function. Primary cilia are important in guiding the process of development, so abnormal ciliary function while an embryo is developing can lead to a set of malformations that can occur regardless of the particular genetic problem. The similarity of the clinical features of these developmental disorders means that they form a recognizable cluster of syndromes, loosely attributed to abnormal ciliary function and hence called ciliopathies. Regardless of the actual genetic cause, it is clustering of a set of characteristic physiological features which define whether a syndrome is a ciliopathy.

<span class="mw-page-title-main">Polycystic kidney disease</span> Congenital disorder of urinary system

Polycystic kidney disease is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts within the kidney. These cysts may begin to develop in utero, in infancy, in childhood, or in adulthood. Cysts are non-functioning tubules filled with fluid pumped into them, which range in size from microscopic to enormous, crushing adjacent normal tubules and eventually rendering them non-functional as well.

<span class="mw-page-title-main">Autosomal recessive polycystic kidney disease</span> Medical condition

Autosomal recessive polycystic kidney disease (ARPKD) is the recessive form of polycystic kidney disease. It is associated with a group of congenital fibrocystic syndromes. Mutations in the PKHD1 cause ARPKD.

<span class="mw-page-title-main">TRPP3</span> Protein-coding gene in the species Homo sapiens

Polycystic kidney disease 2-like 2 protein (PKD2L2) also known as transient receptor potential polycystic 5 (TRPP5) is a protein that in humans is encoded by the PKD2L2 gene.

<span class="mw-page-title-main">GAIN domain</span> Protein domain

The GAIN domain is a protein domain found in a number of cell surface receptors, including adhesion-GPCRs and polycystic kidney disease proteins PKD1 and PKD2. The domain is involved in the self-cleavage of these transmembrane receptors, and has been shown to be crucial for their function. Point mutations within the GAIN domain of PKD1 and GPR56 are known to cause polycystic kidney disease and polymicrogyria, respectively.

The Polycystin Cation Channel (PCC) Family consists of several transporters ranging in size from 500 to over 4000 amino acyl residues (aas) in length and exhibiting between 5 and 18 transmembrane segments (TMSs). This family is a constituent of the Voltage-Gated Ion Channel (VIC) Superfamily. These transporters generally catalyze the export of cations. A representative list of proteins belonging to the PCC family can be found in the Transporter Classification Database.

<span class="mw-page-title-main">Polycystic kidney disease 3 (autosomal dominant)</span> Protein in humans

Polycystic kidney disease 3 (autosomal dominant) is a protein that in humans is encoded by the PKD3 gene.

<span class="mw-page-title-main">PRKX</span> Protein-coding gene in the species Homo sapiens

Protein kinase, X-linked is a protein that in humans is encoded by the PRKX gene.

RVxP motif is a protein motif involved in localizing proteins into cilia.

Shrawan Kumar, is an Indian-American geneticist, working in the fields of molecular and population genetics. He is known for his contributions in the discovery of two genes related to Branchio-oto-renal syndrome (BOR) and Autosomal Dominant Polycystic Kidney Disease (ADPKD2).

References

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  12. 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.
  13. 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.
  14. Shi Y, Mei C, Zhou Q, Wang T, Yu S, Lei J, Ge X, Hu F, Su Q (2018-09-07). "Structure of the human PKD1-PKD2 complex". Science. 361 (6406): eaat9819. doi: 10.1126/science.aat9819 . ISSN   0036-8075. PMID   30093605.
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  16. "Entrez Gene: PKD1 polycystic kidney disease 1 (autosomal dominant)".