Polycystin cation channel family
| C-terminal Cytosolic Domain of Polycystin-2 | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| Symbol | PKD2 | ||||||||
| Pfam | PF08016 | ||||||||
| InterPro | IPR013122 | ||||||||
| TCDB | 1.A.5 | ||||||||
| OPM superfamily | 8 | ||||||||
| OPM protein | 5mkf | ||||||||
| |||||||||
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]
Crystal Structures[edit]
There are a number of crystal structures available for members of the PCC family. Some of these include:
Polycystic kidney disease 2-like 1 protein: PDB: 3TE3, 4GIF
PKD2: PDB: 2KLD, 2KLE, 3HRN, 3HRO, 2KQ6, 2Y4Q
Homologues[edit]
Human polycystin[edit]
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[edit]
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[edit]
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[edit]
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[edit]
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[edit]
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[edit]
References[edit]
- ^ "1.A.5 The Polycystin Cation Channel (PCC) Family". TCDB. Retrieved 10 April 2016.
- ^ "P98161-PKD1 Human". Uniprot.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Noben-Trauth K (1 January 2011). "The TRPML3 Channel: From Gene to Function". Transient Receptor Potential Channels. Advances in Experimental Medicine and Biology. Vol. 704. pp. 229–37. doi:10.1007/978-94-007-0265-3_13. ISBN 978-94-007-0264-6. PMID 21290299.
- ^ a b 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.
- ^ 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.
- ^ 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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