Polycystin cation channel family

C-terminal Cytosolic Domain of Polycystin-2

Solution Structure of the Calcium Binding Domain of the C-terminal Cytosolic Domain of Polycystin-2
Identifiers
Symbol PKD2
Pfam PF08016
InterPro IPR013122
TCDB 1.A.5

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

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]

See also

References

  1. ↑ "1.A.5 The Polycystin Cation Channel (PCC) Family". TCDB. Retrieved 2016-04-10.
  2. ↑ Oatley, Peter; Stewart, Andrew P.; Sandford, Richard; Edwardson, J. Michael (2012-04-03). "Atomic force microscopy imaging reveals the domain structure of polycystin-1". Biochemistry 51 (13): 2879–2888. doi:10.1021/bi300134b. ISSN 1520-4995. PMID 22409330.
  3. ↑ Dalagiorgou, Georgia; Basdra, Efthimia K.; Papavassiliou, Athanasios G. (2010-10-01). "Polycystin-1: function as a mechanosensor". The International Journal of Biochemistry & Cell Biology 42 (10): 1610–1613. doi:10.1016/j.biocel.2010.06.017. ISSN 1878-5875. PMID 20601082.
  4. ↑ Molland, Katrina L.; Narayanan, Anoop; Burgner, John W.; Yernool, Dinesh A. (2010-07-01). "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): 171–183. doi:10.1042/BJ20091843. ISSN 1470-8728. PMID 20408813.
  5. ↑ Anyatonwu, Georgia I.; Ehrlich, Barbara E. (2005-08-19). "Organic cation permeation through the channel formed by polycystin-2". The Journal of Biological Chemistry 280 (33): 29488–29493. doi:10.1074/jbc.M504359200. ISSN 0021-9258. PMID 15961385.
  6. ↑ Gonzalez-Perrett, Silvia; Batelli, Marisa; Kim, Keetae; Essafi, Makram; Timpanaro, Gustavo; Moltabetti, Nicolas; Reisin, Ignacio L.; Arnaout, M. Amin; Cantiello, Horacio F. (2002-07-12). "Voltage dependence and pH regulation of human polycystin-2-mediated cation channel activity". The Journal of Biological Chemistry 277 (28): 24959–24966. doi:10.1074/jbc.M105084200. ISSN 0021-9258. PMID 11991947.
  7. ↑ Liu, Yan; Li, Qiang; Tan, Miao; Zhang, Yu-Yang; Karpinski, Edward; Zhou, Jing; Chen, Xing-Zhen (2002-08-14). "Modulation of the human polycystin-L channel by voltage and divalent cations". FEBS letters 525 (1-3): 71–76. ISSN 0014-5793. PMID 12163164.
  8. ↑ Xu, G. Mark; González-Perrett, Silvia; Essafi, Makram; Timpanaro, Gustavo A.; Montalbetti, Nicolás; Arnaout, M. Amin; Cantiello, Horacio F. (2003-01-17). "Polycystin-1 activates and stabilizes the polycystin-2 channel". The Journal of Biological Chemistry 278 (3): 1457–1462. doi:10.1074/jbc.M209996200. ISSN 0021-9258. PMID 12407099.
  9. ↑ Noben-Trauth, Konrad (2011-01-01). "The TRPML3 channel: from gene to function". Advances in Experimental Medicine and Biology 704: 229–237. doi:10.1007/978-94-007-0265-3_13. ISSN 0065-2598. PMID 21290299.
  10. ↑ Li, Qiang; Dai, Xiao-Qing; Shen, Patrick Y.; Wu, Yuliang; Long, Wentong; Chen, Carl X.; Hussain, Zahir; Wang, Shaohua; Chen, Xing-Zhen (2007-12-01). "Direct binding of alpha-actinin enhances TRPP3 channel activity". Journal of Neurochemistry 103 (6): 2391–2400. doi:10.1111/j.1471-4159.2007.04940.x. ISSN 1471-4159. PMID 17944866.
  11. ↑ Kiselyov, Kirill; Chen, Jin; Rbaibi, Youssef; Oberdick, Daniel; Tjon-Kon-Sang, Sandra; Shcheynikov, Nikolay; Muallem, Shmuel; Soyombo, Abigail (2005-12-30). "TRP-ML1 is a lysosomal monovalent cation channel that undergoes proteolytic cleavage". The Journal of Biological Chemistry 280 (52): 43218–43223. doi:10.1074/jbc.M508210200. ISSN 0021-9258. PMID 16257972.
  12. ↑ Li, Qiang; Dai, Xiao-Qing; Shen, Patrick Y.; Wu, Yuliang; Long, Wentong; Chen, Carl X.; Hussain, Zahir; Wang, Shaohua; Chen, Xing-Zhen (2007-12-01). "Direct binding of alpha-actinin enhances TRPP3 channel activity". Journal of Neurochemistry 103 (6): 2391–2400. doi:10.1111/j.1471-4159.2007.04940.x. ISSN 1471-4159. PMID 17944866.
  13. ↑ Kim, Ingyu; Fu, Yulong; Hui, Kwokyin; Moeckel, Gilbert; Mai, Weiyi; Li, Cunxi; Liang, Dan; Zhao, Ping; Ma, Jie (2008-03-01). "Fibrocystin/polyductin modulates renal tubular formation by regulating polycystin-2 expression and function". Journal of the American Society of Nephrology: JASN 19 (3): 455–468. doi:10.1681/ASN.2007070770. ISSN 1533-3450. PMC 2391052. PMID 18235088.

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