Polycystin cation channel family

Last updated
C-terminal Cytosolic Domain of Polycystin-2
Identifiers
SymbolPKD2
Pfam PF08016
InterPro IPR013122
TCDB 1.A.5
OPM superfamily 8
OPM protein 5mkf
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

The Polycystin Cation Channel (PCC) Family (TC# 1.A.5) 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. [1]

Contents

Crystal Structures

There are a number of crystal structures available for members of the PCC family. Some of these include:

PKD1: PDB: 1B4R ​

Polycystic kidney disease 2-like 1 protein: PDB: 3TE3 ​, 4GIF ​

PKD2: PDB: 2KLD ​, 2KLE ​, 3HRN ​, 3HRO ​, 2KQ6 ​, 2Y4Q ​

Homologues

Human polycystin

Human polycystin 1 is a huge protein of 4303 amino acyl residues (aas). Its repeated leucine-rich (LRR) segment is found in many proteins. According to the UniProt description, polycystin 1 contains 16 polycystic kidney disease (PKD) domains, one LDL-receptor class A domain, one C-type lectin family domain, and 16-18 putative TMSs in positions between residues 2200 and 4100. [2] However, atomic force microscopy imaging has revealed the domain structure of polycystin-1. [3] It exhibits minimal sequence similarities, but similar domain organization and membrane topology with established cation channels such as the transient receptor potential (TRP) and voltage-gated ion channel (VIC) family proteins (TC# 1.A.4 and TC# 1.A.1, respectively). However, PSI-BLAST without iterations does not pick up these similarities. The PKD2L1-PKD1L3 complex perceives sour taste. Disruption of the PKD2-PKD1 complex, responsible for mechanosensation, leads to development of ADPKD (autosomal-dominant polycystic kidney disease). [4] Besides modulating channel activity and related signaling events, the CRDs (C-terminal regulatory domains) of PKD2 and PKD2L1 play a central role in channel oligomerization. These proteins appear to form trimers. [5]

Polycystin-L

Polycystin-L has been shown to be a cation (Na+, K+ and Ca2+) channel that is activated by Ca2+, while polycystin-2 has been characterized as a Ca2+-permeable cation-selective channel. Two members of the PCC family (polycystin 1 and 2; PKD1 and 2) are mutated in human autosomal dominant polycystic kidney disease, and polycystin-L, very similar and probably orthologous to PKD2, is deleted in mice with renal and retinal defects. PKD1 and 2 interact to form the non-selective cation channel in vitro, but PKD2 can form channels in the absence of any other associated protein. Polycystin-2 transports a variety of organic cations (dimethylamine, tetraethylammonium, tetrabutylammonium, tetrapropylammonium, tetrapentenyl ammonium). The channel diameter was estimated to be at least 1.1 Å. [6] Both are reported to be integral membrane proteins with 7-11 TMSs (PKD1) and 6 TMSs (PKD2), respectively. They share a homologous region of about 400 residues (residues 206-623 in PKD2; residues 3656-4052 in PKD1) which includes five TMSs of both proteins. This may well be the channel domain. PKD2 and polycystin-L have been shown to exhibit voltage-, pH- and divalent cation-dependent channel activity. [7] [8] PKD1 may function primarily in regulation, both activating and stabilizing the polycystin-2 channel. [9]

Transient receptor potential proteins

Transient receptor potential (TRP) polycystin 2 and 3 (TRPP2 and 3) are homologous members of the TRP superfamily of cation channels but have different physiological functions. TRPP2 is part of a flow sensor, and is defective in autosomal dominant polycystic kidney disease and implicated in left-right asymmetry development. TRPP3 is implicated in sour tasting in bipolar cells of taste buds of the tongue and in the regulation of pH-sensitive action potential in neurons surrounding the central canal of the spinal cord. TRPP3 is present in both excitable and non-excitable cells in various tissues, such as retina, brain, heart, testis, and kidney. [10] [11]

Mucolipin-1

The TRP-ML1 protein (Mucolipin-1) has been shown to be a lysosomal monovalent cation channel that undergoes inactivating proteolytic cleavage. [12] It shows greater sequence similarity to the transmembrane region of polycystin 2 than it does to members of the TRP-CC family (TC# 1.A.4). Therefore, it is included in the former family. Both the PCC and TRP-CC families are members of the VIC superfamily.

Alpha-actinin

Alpha-actinin is an actin-bundling protein known to regulate several types of ion channels. Planer lipid bilayer electrophysiology showed that TRPP3 exhibits cation channel activities that are substantially augmented by alpha-actinin. The TRPP3-alpha-actinin association was documented by co-immunoprecipitation using native cells and tissues, yeast two-hybrid, and in vitro binding assays. [11] TRPP3 is abundant in mouse brain where it associates with alpha-actinin-2. Alpha-actinin attaches TRPP3 to the cytoskeleton and up-regulates its channel function.

Physiological significance

Autosomal recessive polycystic kidney disease is caused by mutations in PKHD1, which encodes the membrane-associated receptor-like protein fibrocystin/polyductin (FPC) (Q8TCZ9, 4074aaa). FPC associates with the primary cilia of epithelial cells and co-localizes with the Pkd2 gene product polycystin-2 (PC2). Kim et al. (2008) have concluded that a functional and molecular interaction exists between FPC and PC2 in vivo. [13]

See also

Related Research Articles

<span class="mw-page-title-main">Ion channel</span> Pore-forming membrane protein

Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.

<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.

Transient receptor potential channels are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. Most of these are grouped into two broad groups: Group 1 includes TRPC, TRPV, TRPVL, TRPM, TRPS, TRPN, and TRPA. Group 2 consists of TRPP and TRPML. Other less-well categorized TRP channels exist, including yeast channels and a number of Group 1 and Group 2 channels present in non-animals. Many of these channels mediate a variety of sensations such as pain, temperature, different kinds of tastes, pressure, and vision. In the body, some TRP channels are thought to behave like microscopic thermometers and used in animals to sense hot or cold. Some TRP channels are activated by molecules found in spices like garlic (allicin), chili pepper (capsaicin), wasabi ; others are activated by menthol, camphor, peppermint, and cooling agents; yet others are activated by molecules found in cannabis or stevia. Some act as sensors of osmotic pressure, volume, stretch, and vibration. Most of the channels are activated or inhibited by signaling lipids and contribute to a family of lipid-gated ion channels.

<span class="mw-page-title-main">Chloride channel</span> Class of transport proteins

Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration in vivo is much higher than other anions. Several families of voltage-gated channels and ligand-gated channels have been characterized in humans.

<span class="mw-page-title-main">Inward-rectifier potassium channel</span> Group of transmembrane proteins that passively transport potassium ions

Inward-rectifier potassium channels (Kir, IRK) are a specific lipid-gated subset of potassium channels. To date, seven subfamilies have been identified in various mammalian cell types, plants, and bacteria. They are activated by phosphatidylinositol 4,5-bisphosphate (PIP2). The malfunction of the channels has been implicated in several diseases. IRK channels possess a pore domain, homologous to that of voltage-gated ion channels, and flanking transmembrane segments (TMSs). They may exist in the membrane as homo- or heterooligomers and each monomer possesses between 2 and 4 TMSs. In terms of function, these proteins transport potassium (K+), with a greater tendency for K+ uptake than K+ export. The process of inward-rectification was discovered by Denis Noble in cardiac muscle cells in 1960s and by Richard Adrian and Alan Hodgkin in 1970 in skeletal muscle cells.

<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.

TRPML comprises a group of three evolutionarily related proteins that belongs to the large family of transient receptor potential ion channels. The three proteins TRPML1, TRPML2 and TRPML3 are encoded by the mucolipin-1 (MCOLN1), mucolipin-2 (MCOLN2) and mucolipin-3 (MCOLN3) genes, respectively.

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

<span class="mw-page-title-main">Polycystin 1</span> Family of transport proteins

Polycystin 1 (PC1) is a protein that in humans is encoded by the PKD1 gene. 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.

<span class="mw-page-title-main">TRPC1</span> Protein and coding gene in humans

Transient receptor potential canonical 1 (TRPC1) is a protein that in humans is encoded by the TRPC1 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">Zinc-dependent phospholipase C</span>

In molecular biology, zinc-dependent phospholipases C is a family of bacterial phospholipases C enzymes, some of which are also known as alpha toxins.

<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">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.

PKD domain was first identified in the polycystic kidney disease protein, polycystin-1, and contains an Ig-like fold consisting of a beta-sandwich of seven strands in two sheets with a Greek key topology, although some members have additional strands. Polycystin-1 is a large cell-surface glycoprotein involved in adhesive protein–protein and protein–carbohydrate interactions; however it is not clear if the PKD domain mediates any of these interactions.

The transient receptor potential Ca2+ channel (TRP-CC) family (TC# 1.A.4) is a member of the voltage-gated ion channel (VIC) superfamily and consists of cation channels conserved from worms to humans. The TRP-CC family also consists of seven subfamilies (TRPC, TRPV, TRPM, TRPN, TRPA, TRPP, and TRPML) based on their amino acid sequence homology:

  1. the canonical or classic TRPs,
  2. the vanilloid receptor TRPs,
  3. the melastatin or long TRPs,
  4. ankyrin (whose only member is the transmembrane protein 1 [TRPA1])
  5. TRPN after the nonmechanoreceptor potential C (nonpC), and the more distant cousins,
  6. the polycystins
  7. and mucolipins.

The K+Transporter (Trk) Family is a member of the voltage-gated ion channel (VIC) superfamily. The proteins of the Trk family are derived from Gram-negative and Gram-positive bacteria, yeast and plants.

<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.

References

  1. ↑ "1.A.5 The Polycystin Cation Channel (PCC) Family". TCDB. Retrieved 10 April 2016.
  2. ↑ "P98161-PKD1 Human". Uniprot.
  3. ↑ Oatley P, Stewart AP, Sandford R, Edwardson JM (April 2012). "Atomic force microscopy imaging reveals the domain structure of polycystin-1". Biochemistry. 51 (13): 2879–88. doi:10.1021/bi300134b. PMID   22409330.
  4. ↑ 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.
  5. ↑ Molland KL, Narayanan A, Burgner JW, Yernool DA (July 2010). "Identification of the structural motif responsible for trimeric assembly of the C-terminal regulatory domains of polycystin channels PKD2L1 and PKD2". The Biochemical Journal. 429 (1): 171–83. doi:10.1042/BJ20091843. PMID   20408813.
  6. ↑ Anyatonwu GI, Ehrlich BE (August 2005). "Organic cation permeation through the channel formed by polycystin-2". The Journal of Biological Chemistry. 280 (33): 29488–93. doi: 10.1074/jbc.M504359200 . PMID   15961385.
  7. ↑ Gonzalez-Perrett S, Batelli M, Kim K, Essafi M, Timpanaro G, Moltabetti N, Reisin IL, Arnaout MA, Cantiello HF (July 2002). "Voltage dependence and pH regulation of human polycystin-2-mediated cation channel activity". The Journal of Biological Chemistry. 277 (28): 24959–66. doi: 10.1074/jbc.M105084200 . PMID   11991947.
  8. ↑ Liu Y, Li Q, Tan M, Zhang YY, Karpinski E, Zhou J, Chen XZ (August 2002). "Modulation of the human polycystin-L channel by voltage and divalent cations". FEBS Letters. 525 (1–3): 71–6. doi: 10.1016/s0014-5793(02)03071-5 . PMID   12163164. S2CID   3150744.
  9. ↑ Xu GM, González-Perrett S, Essafi M, Timpanaro GA, Montalbetti N, Arnaout MA, Cantiello HF (January 2003). "Polycystin-1 activates and stabilizes the polycystin-2 channel". The Journal of Biological Chemistry. 278 (3): 1457–62. doi:10.1074/jbc.M209996200. PMID   12407099.
  10. ↑ Noben-Trauth K (1 January 2011). "The TRPML3 channel: from gene to function". Advances in Experimental Medicine and Biology. 704: 229–37. doi:10.1007/978-94-007-0265-3_13. ISBN   978-94-007-0264-6. PMID   21290299.
  11. 1 2 Li Q, Dai XQ, Shen PY, Wu Y, Long W, Chen CX, Hussain Z, Wang S, Chen XZ (December 2007). "Direct binding of alpha-actinin enhances TRPP3 channel activity". Journal of Neurochemistry. 103 (6): 2391–400. doi: 10.1111/j.1471-4159.2007.04940.x . PMID   17944866. S2CID   84357640.
  12. ↑ Kiselyov K, Chen J, Rbaibi Y, Oberdick D, Tjon-Kon-Sang S, Shcheynikov N, Muallem S, Soyombo A (December 2005). "TRP-ML1 is a lysosomal monovalent cation channel that undergoes proteolytic cleavage". The Journal of Biological Chemistry. 280 (52): 43218–23. doi: 10.1074/jbc.M508210200 . PMID   16257972.
  13. ↑ Kim I, Fu Y, Hui K, Moeckel G, Mai W, Li C, Liang D, Zhao P, Ma J, Chen XZ, George AL, Coffey RJ, Feng ZP, Wu G (March 2008). "Fibrocystin/polyductin modulates renal tubular formation by regulating polycystin-2 expression and function". Journal of the American Society of Nephrology. 19 (3): 455–68. doi:10.1681/ASN.2007070770. PMC   2391052 . PMID   18235088.

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