Polycystin cation channel family

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]

C-terminal Cytosolic Domain of Polycystin-2
Identifiers
SymbolPKD2
PfamPF08016
InterProIPR013122
TCDB1.A.5
OPM superfamily8
OPM protein5mkf

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 SwissProt 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. However, atomic force microscopy imaging has revealed the domain structure of polycystin-1.[2] 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).[3] 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.[4]

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.[5] 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.[6][7] PKD1 may function primarily in regulation, both activating and stabilizing the polycystin-2 channel.[8]

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.[9][10]

Mucolipin-1

The TRP-ML1 protein (Mucolipin-1) has been shown to be a lysosomal monovalent cation channel that undergoes inactivating proteolytic cleavage.[11] 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.[12] 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]

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See also

References
  1. "1.A.5 The Polycystin Cation Channel (PCC) Family". TCDB. Retrieved 10 April 2016.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  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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