1.A.5 The Polycystin Cation Channel (PCC) Family

Polycystic kidney disease (PKD), comprising autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD), is characterized by incessant cyst formation in the kidneys and liver. ADPKD and ARPKD represent the leading genetic causes of renal disease in adults and children, respectively. ADPKD is caused by mutations in PKD1 encoding polycystin1 (PC1) and PKD2 encoding polycystin 2 (PC2). PC1/2 are multi-pass transmembrane proteins that form a complex localized in the primary cilium. Predominant ARPKD cases are caused by mutations in polycystic kidney and hepatic disease 1 (PKHD1) gene that encodes the Fibrocystin/Polyductin (FPC) protein, whereas a small subset of cases are caused by mutations in DAZ interacting zinc finger protein 1 like (DZIP1L) gene (Ma 2021).

Human polycystin 1 (PC1) is a huge protein of 4303 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 (Oatley et al., 2012). 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#s 1.A.4 and 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) (Dalagiorgou et al. 2010). Polycystic kidney disease is an inherited degenerative disease in which the uriniferous tubules are replaced by expanding fluid-filled cysts that ultimately destroy organ function (Smith et al. 2021).

 Besides modulating channel activity and related signalling events, the CRDs (C-terminal regulatory domains) of PKD2 and PKD2L1 play a central role in channel oligomerization. These proteins appear to form trimers (Molland et al. 2010). Polycystin-1 is a possible receptor, able to sense extracellular stiffness and to negatively control the cellular actomyosin contraction machinery. Nigro and Boletta 2021 reviewed the literature on autosomal dominant polycystic kidney disease, providing a mechanistic view on the topic.

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 (Anyatonwu and Ehrlich, 2005). 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 (Gonzalez-Perrett et al., 2002; Liu et al., 2002). PKD1 may function primarily in regulation, both activating and stabilizing the polycystin-2 channel (Xu et al., 2003).

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; TRPP2).  Kim et al.  (2008) have concluded that a functional and molecular interaction exists between FPC and PC2 in vivo. Mutations in polycystin-1 and transient receptor potential polycystin 2 (TRPP2) account for almost all clinically identified cases of autosomal dominant polycystic kidney disease (ADPKD), one of the most common human genetic diseases. TRPP2 functions as a cation channel in its homomeric complex and in the TRPP2/polycystin-1 receptor/ion channel complex (Arif Pavel et al. 2016).

Humans have five PKD1 proteins, whereas sea urchins have 10. The PKD1 proteins of the sea urchin, Strongylocentrotus purpuratus, are referred to as the Receptor for Egg Jelly, or SpREJ proteins. SpREJ proteins form a subfamily within the PKD1 family. They frequently contain C-type lectin domains, PKD repeats, a REJ domain, a GPS domain, a PLAT/LH2 domain, 1-11 transmembrane segments and a C-terminal coiled-coil domain. SpREJs show distinct patterns of expression during embryogenesis, and adult tissues show tissue-specific patterns of SpREJ expression (Gunaratne et al. 2007).

The TRP-ML1 protein (Mucolipin-1) has been shown to be a lysosomal monovalent cation channel that undergoes inactivating proteolytic cleavage (Kiselyov et al., 2005). It shows greater sequence similarity to the transmembrane region of polycystin 2 than it does to members of the TRP-CC family (1.A.4). Therefore, it is included in the former family. Both the PCC and TRP-CC families are members of the VIC superfamily.

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.

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 (Li et al., 2007). 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.

Renal cysts, which arise from renal tubules, can be seen in a variety of hereditary and nonhereditary entities. Common mechanisms associated with renal cyst formation include increased cell proliferation, epithelial fluid secretion, and extracellular matrix remodeling (Ghata and Cowley 2017). Hereditary polycystic kidney disease (PKD) is seen as a component of numerous diseases. Autosomal dominant (AD) PKD is the most common potentially fatal hereditary disease in humans, causes renal failure in approximately 50% of affected individuals, and accounts for approximately 5% of end stage renal disease cases in the United States. ADPKD is caused by mutation in one of two genes-85% of cases are caused by mutation in PKD1 on chromosome 16, and 15% of cases are caused by mutation in PKD2 on chromosome 4. Polycystin-1, encoded by PKD1, is a large protein, has multiple transmembrane spanning domains, has extracellular regions suggesting a role in cell-cell or cell-matrix interactions, has intracellular domains suggesting a role in signal transduction, and can physically interact with Polycystin-2. Polycystin-2 is smaller, has transmembrane domains, can act as a cation channel with calcium permeability, and may be regulated by Polycystin-1. These proteins, and many others associated with cystic kidney disease, localize to primary cilia, which may act as flow sensors in the kidney; cystic kidney diseases have also been termed ciliopathies (Ghata and Cowley 2017).

Mutations in polycystin-1 (PC1) and PC2 result in ADPKD, characterized by the formation and development of kidney cysts as has been reviewed by Lemos and Ehrlich 2017. Epithelial cells with loss-of-function of PC1 or PC2 show higher rates of proliferation and apoptosis and reduced autophagy. PC1 serves as a sensor that is usually found in complex with PC2, the calcium-permeable cation channel of the system. In addition to decreased Ca2+ signaling, several other cell fate-related pathways are de-regulated in ADPKD, including cAMP, MAPK, Wnt, JAK-STAT, Hippo, Src, and mTOR. In their review, Lemos and Ehrlich 2017  discuss how polycystins regulate cell death and survival, highlighting the complexity of molecular cascades that are involved in ADPKD. Canonical and noncanonical signaling pathways have been reviewed with emphasis on which heterotrimeric G proteins are involved in the pathological reorganization of the tubular epithelial cell architecture to exacerbate renal cystogenic pathways (Hama and Park 2016).

PC1, PC2 and fibrocystin proteins, the respective products of the PKD1, PKD2 and PKHD1 genes, are abundant in urinary exosome-like vesicles (ELVs) where they form the polycystin complex (PCC). ELVs are 100 nm diameter membrane vesicles shed into the urine by the cells lining the nephron (Lea et al. 2020). The three major human cystogene proteins are detectable in human urinary ELVs and that all three undergo post-translational proteolytic processing (Lea et al. 2020).

PCC proteins catalyze:

Cations (in) Cations (out)

This family belongs to the Leucine-rich Repeat-containing Domain (LRRD) Superfamily.



Altamirano, F., G.G. Schiattarella, K.M. French, S.Y. Kim, F. Engelberger, S. Kyrychenko, E. Villalobos, D. Tong, J.W. Schneider, C.A. Ramirez-Sarmiento, S. Lavandero, T.G. Gillette, and J.A. Hill. (2019). Polycystin-1 Assembles with Kv Channels to Govern Cardiomyocyte Repolarization and Contractility. Circulation. [Epub: Ahead of Print]

Anyatonwu, G.I. and B.E. Ehrlich. (2005). Organic cation permeation through the channel formed by polycystin-2. J. Biol. Chem. 280: 29488-29493.

Arif Pavel, M., C. Lv, C. Ng, L. Yang, P. Kashyap, C. Lam, V. Valentino, H.Y. Fung, T. Campbell, S.G. Møller, D. Zenisek, N.G. Holtzman, and Y. Yu. (2016). Function and regulation of TRPP2 ion channel revealed by a gain-of-function mutant. Proc. Natl. Acad. Sci. USA 113: E2363-2372.

Bai, C.X., S. Kim, W.P. Li, A.J. Streets, A.C. Ong, and L. Tsiokas. (2008). Activation of TRPP2 through mDia1-dependent voltage gating. EMBO. J. 27: 1345-1356.

Bycroft, M., A. Bateman, J. Clarke, S.J. Hamill, R. Sandford, R.L. Thomas, and C. Chothia. (1999). The structure of a PKD domain from polycystin-1. Implications for polycystic kidney disease. EMBO J. 18: 297-305.

Chen, X.-Z., P.M. Vassilev, N. Basora, J.-B. Peng, H. Nomura, Y. Segal, E.M. Brown, S.T. Reeders, M.A. Hediger, and J. Zhou. (1999). Polycystin-L is a calcium-regulated cation channel permeable to calcium ions. Nature 401: 383-386.

Cuajungco MP., Basilio LC., Silva J., Hart T., Tringali J., Chen CC., Biel M. and Grimm C. (2014). Cellular zinc levels are modulated by TRPML1-TMEM163 interaction. Traffic. 15(11):1247-65.

Cuajungco, M.P. and K. Kiselyov. (2017). The mucolipin-1 (TRPML1) ion channel, transmembrane-163 (TMEM163) protein, and lysosomal zinc handling. Front Biosci (Landmark Ed) 22: 1330-1343.

Cuajungco, M.P. and M.A. Samie. (2008). The varitint-waddler mouse phenotypes and the TRPML3 ion channel mutation: cause and consequence. Pflugers Arch 457: 463-473.

Cuajungco, M.P., J. Silva, A. Habibi, and J.A. Valadez. (2015). The mucolipin-2 (TRPML2) ion channel: a tissue-specific protein crucial to normal cell function. Pflugers Arch. [Epub: Ahead of Print]

Dalagiorgou, G., E.K. Basdra, and A.G. Papavassiliou. (2010). Polycystin-1: function as a mechanosensor. Int J Biochem. Cell Biol. 42: 1610-1613.

Del Rocío Cantero, M. and H.F. Cantiello. (2022). Polycystin-2 (TRPP2): Ion Channel Properties and Regulation. Gene 146313. [Epub: Ahead of Print]

Deltas, C.C. (2001). Mutations of the human polycystic kidney disease 2 (PKD2) gene. Hum. Mutat. 18: 13-24.

Dixon, E.E. and O.M. Woodward. (2018). Three-dimensional in vitro models answer the right questions in ADPKD cystogenesis. Am. J. Physiol. Renal Physiol 315: F332-F335.

Dong, X.P., X. Cheng, E. Mills, M. Delling, F. Wang, T. Kurz, and H. Xu. (2008). The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature 455: 992-996.

Freeman, S.A., S. Uderhardt, A. Saric, R.F. Collins, C.M. Buckley, S. Mylvaganam, P. Boroumand, J. Plumb, R.N. Germain, D. Ren, and S. Grinstein. (2020). Lipid-gated monovalent ion fluxes regulate endocytic traffic and support immune surveillance. Science 367: 301-305.

García-Añoveros, J. and T. Wiwatpanit. (2014). TRPML2 and Mucolipin Evolution. Handb Exp Pharmacol 222: 647-658.

Ghata, J. and B.D. Cowley, Jr. (2017). Polycystic Kidney Disease. Compr Physiol 7: 945-975.

González-Perrett, S., K. Kim, C. Ibarra, A.E. Damiano, E. Zotta, M. Batelli, P.C. Harris, I.L. Reisin, M.A. Arnaout, and H.F. Cantiello. (2001). Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel. Proc. Natl. Acad. Sci. USA 98: 1182-1187.

Gonzalez-Perrett, S., M. Batelli, K. Kim, M. Essafi, G. Timpanaro, N. Moltabetti, I.L. Reisin, M.A. Arnaout, and H.F. Cantiello. (2002). Voltage dependence and pH regulation of human polycystin-2-mediated cation channel activity. J. Biol. Chem. 277: 24959-24966.

Gunaratne, H.J., G.W. Moy, M. Kinukawa, S. Miyata, S.A. Mah, and V.D. Vacquier. (2007). The 10 sea urchin receptor for egg jelly proteins (SpREJ) are members of the polycystic kidney disease-1 (PKD1) family. BMC Genomics 8: 235.

Hama, T. and F. Park. (2016). Heterotrimeric G protein signaling in polycystic kidney disease. Physiol Genomics 48: 429-445.

Hayashi, T., K. Hosono, A. Kubo, K. Kurata, S. Katagiri, K. Mizobuchi, M. Kurai, N. Mamiya, M. Kondo, T. Tachibana, H. Saitsu, T. Ogata, T. Nakano, and Y. Hotta. (2020). Long-term observation of a Japanese mucolipidosis IV patient with a novel homozygous p.F313del variant of MCOLN1. Am J Med Genet A. [Epub: Ahead of Print]

Higashihara, E., S. Horie, M. Kinoshita, P.C. Harris, T. Okegawa, M. Tanbo, H. Hara, T. Yamaguchi, K. Shigemori, H. Kawano, I. Miyazaki, S. Kaname, and K. Nutahara. (2018). A potentially crucial role of the PKD1 C-terminal tail in renal prognosis. Clin Exp Nephrol 22: 395-404.

Hoffmeister, H., A.R. Gallagher, A. Rascle, and R. Witzgall. (2010). The human polycystin-2 protein represents an integral membrane protein with six membrane-spanning domains and intracellular N- and C-termini. Biochem. J. 433: 285-294.

Hogan, M.C., J.L. Bakeberg, V.G. Gainullin, M.V. Irazabal, A.J. Harmon, J.C. Lieske, M.C. Charlesworth, K.L. Johnson, B.J. Madden, R.M. Zenka, D.J. McCormick, J.L. Sundsbak, C.M. Heyer, V.E. Torres, P.C. Harris, and C.J. Ward. (2015). Identification of Biomarkers for PKD1 Using Urinary Exosomes. J Am Soc Nephrol 26: 1661-1670.

Hu, M., Y. Liu, J. Wu, and X. Liu. (2015). Influx-Operated Ca2+ Entry via PKD2-L1 and PKD1-L3 Channels Facilitates Sensory Responses to Polymodal Transient Stimuli. Cell Rep 13: 798-811.

Huang, K., D.R. Diener, A. Mitchell, G.J. Pazour, G.B. Witman, and J.L. Rosenbaum. (2007). Function and dynamics of PKD2 in Chlamydomonas reinhardtii flagella. J. Cell Biol. 179: 501-514.

Hussein, S., W. Zheng, C. Dyte, Q. Wang, J. Yang, F. Zhang, J. Tang, Y. Cao, and X.Z. Chen. (2015). Acid-induced off-response of PKD2L1 channel in Xenopus oocytes and its regulation by Ca(2.). Sci Rep 5: 15752.

Ishimaru, Y., H. Inada, M. Kubota, H. Zhuang, M. Tominaga, and H. Matsunami. (2006). Transient receptor potential family members PKD1L3 and PKD2L1 form a candidate sour taste receptor. Proc. Natl. Acad. Sci. USA 103: 12569-12574.

Ishimaru, Y., Y. Katano, K. Yamamoto, M. Akiba, T. Misaka, R.W. Roberts, T. Asakura, H. Matsunami, and K. Abe. (2010). Interaction between PKD1L3 and PKD2L1 through their transmembrane domains is required for localization of PKD2L1 at taste pores in taste cells of circumvallate and foliate papillae. FASEB J. 24: 4058-4067.

Katoh, T.A., T. Omori, K. Mizuno, X. Sai, K. Minegishi, Y. Ikawa, H. Nishimura, T. Itabashi, E. Kajikawa, S. Hiver, A.H. Iwane, T. Ishikawa, Y. Okada, T. Nishizaka, and H. Hamada. (2023). Immotile cilia mechanically sense the direction of fluid flow for left-right determination. Science 379: 66-71.

Kim H.J., Q. Li, S. Tjon-Kon-Sang, I. So, K. Kiselyov, S. Muallem. (2007). Gain-of-function mutation in TRPML3 causes the mouse Varitint-Waddler phenotype. J Biol Chem. 282: 36138-36142.

Kim HJ., Yamaguchi S., Li Q., So I. and Muallem S. (2010). Properties of the TRPML3 channel pore and its stable expansion by the Varitint-Waddler-causing mutation. J Biol Chem. 285(22):16513-20.

Kim, I., Y. Fu, K. Hui, G. Moeckel, W. Mai, C. Li, D. Liang, P. Zhao, J. Ma, X.Z. Chen, A.L. George, R.J. Coffey, Z.P. Feng, and G. Wu (2008). Fibrocystin/polyductin modulates renal tubular formation by regulating polycystin-2 expression and function. J Am Soc Nephrol 19: 455-68.

Kiselyov, K., J. Chen, Y. Rbaibi, D. Oberdick, S. Tjon-Kon-Sang, N. Shcheynikov, S. Muallem, and A. Soyombo. (2005). TRP-ML1 is a lysosomal monovalent cation channel that undergoes proteolytic cleavage. J. Biol. Chem. 280: 43218-43223.

Kleene, S.J. and N.K. Kleene. (2017). The native TRPP2-dependent channel of murine renal primary cilia. Am. J. Physiol. Renal Physiol 312: F96-F108.

Köttgen, M., B. Buchholz, M.A. Garcia-Gonzalez, F. Kotsis, X. Fu, M. Doerken, C. Boehlke, D. Steffl, R. Tauber, T. Wegierski, R. Nitschke, M. Suzuki, A. Kramer-Zucker, G.G. Germino, T. Watnick, J. Prenen, B. Nilius, E.W. Kuehn, and G. Walz. (2008). TRPP2 and TRPV4 form a polymodal sensory channel complex. J. Cell Biol. 182: 437-447.

Lal, S., N. Scarinci, P.L. Perez, M.D.R. Cantero, and H.F. Cantiello. (2018). Lipid bilayer-atomic force microscopy combined platform records simultaneous electrical and topological changes of the TRP channel polycystin-2 (TRPP2). PLoS One 13: e0202029.

Lea, W.A., K. McGreal, M. Sharma, S.C. Parnell, L. Zelenchuk, M.C. Charlesworth, B.J. Madden, K.L. Johnson, D.J. McCormick, M.C. Hogan, and C.J. Ward. (2020). Analysis of the polycystin complex (PCC) in human urinary exosome-like vesicles (ELVs). Sci Rep 10: 1500.

Lemos, F.O. and B.E. Ehrlich. (2017). Polycystin and calcium signaling in cell death and survival. Cell Calcium. [Epub: Ahead of Print]

Lev, S., D.A. Zeevi, A. Frumkin, V. Offen-Glasner, G. Bach, and B. Minke. (2010). Constitutive activity of the human TRPML2 channel induces cell degeneration. J. Biol. Chem. 285: 2771-2782.

Li, Q., X.Q. Dai, P.Y. Shen, Y. Wu, W. Long, C.X. Chen, Z. Hussain, S. Wang, and X.Z. Chen. (2007). Direct binding of α-actinin enhances TRPP3 channel activity. J Neurochem 103(6): 2391-2400.

Li, Y., N.G. Santoso, S. Yu, O.M. Woodward, F. Qian, and W.B. Guggino. (2009). Polycystin-1 interacts with inositol 1,4,5-trisphosphate receptor to modulate intracellular Ca2+ signaling with implications for polycystic kidney disease. J. Biol. Chem. 284: 36431-36441.

Liu, X., R. Zhang, M. Fatehi, Y. Wang, W. Long, R. Tian, X. Deng, Z. Weng, Q. Xu, P.E. Light, J. Tang, and X.Z. Chen. (2022). Regulation of PKD2 channel function by TACAN. J. Physiol. [Epub: Ahead of Print]

Liu, Y., Q. Li, M. Tan, Y.-Y. Zhang, E. Karpinski, J. Zhou, and X.-Z. Chen. (2002). Modulation of the human polycystin-L channel by voltage and divalent cations. FEBS Lett. 525: 71-76.

Luzio, J.P., N.A. Bright, and P.R. Pryor. (2007). The role of calcium and other ions in sorting and delivery in the late endocytic pathway. Biochem. Soc. Trans. 35: 1088-1091.

Ma, M. (2021). Cilia and polycystic kidney disease. Semin Cell Dev Biol 110: 139-148.

Maser, R.L., J.P. Calvet, and S.C. Parnell. (2022). The GPCR properties of polycystin-1- A new paradigm. Front Mol Biosci 9: 1035507.

Molland, K.L., A. Narayanan, J.W. Burgner, and D.A. Yernool. (2010). Identification of the structural motif responsible for trimeric assembly of the C-terminal regulatory domains of polycystin channels PKD2L1 and PKD2. Biochem. J. 429: 171-183.

Nauli, S.M., F.J. Alenghat, Y. Luo, E. Williams, P. Vassilev, X. Li, A.E. Elia, W. Lu, E.M. Brown, S.J. Quinn, D.E. Ingber, and J. Zhou. (2003). Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet. 33: 129-137.

Neill, A.T., G.W. Moy, and V.D. Vacquier. (2004). Polycystin-2 associates with the polycystin-1 homolog, suREJ3, and localizes to the acrosomal region of sea urchin spermatozoa. Mol Reprod Dev 67: 472-477.

Ng, L.C.T., T.N. Vien, V. Yarov-Yarovoy, and P.G. DeCaen. (2019). Opening TRPP2 () requires the transfer of gating charges. Proc. Natl. Acad. Sci. USA 116: 15540-15549.

Nigro, E.A. and A. Boletta. (2021). Role of the polycystins as mechanosensors of extracellular stiffness. Am. J. Physiol. Renal Physiol 320: F693-F705.

Nims, N.M., D. Vassmer, and R.L. Maser. (2011). Effect of PKD1 gene missense mutations on polycystin-1 membrane topogenesis. Biochemistry 50: 349-355.

Noben-Trauth, K. (2011). The TRPML3 channel: from gene to function. Adv Exp Med Biol 704: 229-237.

Numata, T., K. Tsumoto, K. Yamada, T. Kurokawa, S. Hirose, H. Nomura, M. Kawano, Y. Kurachi, R. Inoue, and Y. Mori. (2017). Integrative Approach with Electrophysiological and Theoretical Methods Reveals a New Role of S4 Positively Charged Residues in PKD2L1 Channel Voltage-Sensing. Sci Rep 7: 9760.

Oatley, P., A.P. Stewart, R. Sandford, and J.M. Edwardson. (2012). Atomic force microscopy imaging reveals the domain structure of polycystin-1. Biochemistry 51: 2879-2888.

Pawnikar, S., B.S. Magenheimer, E.N. Munoz, R.L. Maser, and Y. Miao. (2022). Mechanism of tethered agonist-mediated signaling by polycystin-1. Proc. Natl. Acad. Sci. USA 119: e2113786119.

Ramírez-Sagredo, A., C. Quiroga, V. Garrido-Moreno, C. López-Crisosto, S. Leiva-Navarrete, I. Norambuena-Soto, J. Ortiz-Quintero, M.C. Díaz-Vesga, W. Perez, T. Hendrickson, V. Parra, Z. Pedrozo, F. Altamirano, M. Chiong, and S. Lavandero. (2021). Polycystin-1 regulates cardiomyocyte mitophagy. FASEB J. 35: e21796.

Salehi-Najafabadi, Z., B. Li, V. Valentino, C. Ng, H. Martin, Y. Yu, Z. Wang, P. Kashyap, and Y. Yu. (2017). Extracellular Loops are Essential For the Assembly and Function of Polycystin Receptor-Ion Channel Complexes. J. Biol. Chem. [Epub: Ahead of Print]

Schmiege, P., M. Fine, and X. Li. (2018). The regulatory mechanism of mammalian TRPMLs revealed by cryo-EM. FEBS J. [Epub: Ahead of Print]

Shen, P.S., X. Yang, P.G. DeCaen, X. Liu, D. Bulkley, D.E. Clapham, and E. Cao. (2016). The Structure of the Polycystic Kidney Disease Channel PKD2 in Lipid Nanodiscs. Cell 167: 763-773.e11.

Smith, A.O., J.A. Jonassen, K.M. Preval, R.J. Davis, and G.J. Pazour. (2021). c-Jun N-terminal kinase (JNK) signaling contributes to cystic burden in polycystic kidney disease. PLoS Genet 17: e1009711.

Somlo, S. and B. Ehrlich. (2001). Human disease: calcium signaling in polycystic kidney disease. Curr. Biol. 11: R356-R360.

Su, Q., F. Hu, X. Ge, J. Lei, S. Yu, T. Wang, Q. Zhou, C. Mei, and Y. Shi. (2018). Structure of the human PKD1-PKD2 complex. Science 361:.

Su, Q., F. Hu, Y. Liu, X. Ge, C. Mei, S. Yu, A. Shen, Q. Zhou, C. Yan, J. Lei, Y. Zhang, X. Liu, and T. Wang. (2018). Cryo-EM structure of the polycystic kidney disease-like channel PKD2L1. Nat Commun 9: 1192.

Tang, Y., J. Yang, W. Zheng, J. Tang, X.Z. Chen, J. Yang, and Z. Wang. (2019). Polycystin-1 Inhibits Cell Proliferation through Phosphatase PP2A/B56. Biomed Res Int 2019: 2582401.

Tang, Y., Z. Wang, J. Yang, W. Zheng, D. Chen, G. Wu, R. Sandford, J. Tang, and X.Z. Chen. (2017). Polycystin-1 inhibits eIF2α phosphorylation and cell apoptosis through a PKR-eIF2α pathway. Sci Rep 7: 11493.

Treusch, S., S. Knuth, S.A. Slaugenhaupt, E. Goldin, B.D. Grant, and H. Fares. (2004). Caenorhabditis elegans functional orthologue of human protein h-mucolipin-1 is required for lysosome biogenesis. Proc. Natl. Acad. Sci. USA 101: 4483-4488.

Viet, K.K., A. Wagner, K. Schwickert, N. Hellwig, M. Brennich, N. Bader, T. Schirmeister, N. Morgner, H. Schindelin, and U.A. Hellmich. (2019). Structure of the Human TRPML2 Ion Channel Extracytosolic/Lumenal Domain. Structure. [Epub: Ahead of Print]

Wang, Q., R.A. Corey, G. Hedger, P. Aryal, M. Grieben, C. Nasrallah, A. Baronina, A.C.W. Pike, J. Shi, E.P. Carpenter, and M.S.P. Sansom. (2019). Lipid Interactions of a Ciliary Membrane TRP Channel: Simulation and Structural Studies of Polycystin-2. Structure. [Epub: Ahead of Print]

Wang, Z., C. Ng, X. Liu, Y. Wang, B. Li, P. Kashyap, H.A. Chaudhry, A. Castro, E.M. Kalontar, L. Ilyayev, R. Walker, R.T. Alexander, F. Qian, X.Z. Chen, and Y. Yu. (2019). The ion channel function of polycystin-1 in the polycystin-1/polycystin-2 complex. EMBO Rep e48336. [Epub: Ahead of Print]

Wilson, P.D. (2001). Polycystin: new aspects of structure, function, and regulation. J. Am. Soc. Nephrol. 12: 834-845.

Wu, G. (2001). Current advances in molecular genetics of autosomal-dominant polycystic kidney disease. Curr. Opin. Nephrol. Hypertens. 10: 23-31.

Xu, G.M., S. González-Perrett, M. Essafi, G.A. Timpanaro, N. Montalbetti, M.A. Arnaout, and H.F. Cantiello. (2003). Polycystin-1 activates and stabilizes the polycystin-2 channel. J. Biol. Chem. 278: 1457-1462.

Yoshiba, S., H. Shiratori, I.Y. Kuo, A. Kawasumi, K. Shinohara, S. Nonaka, Y. Asai, G. Sasaki, J.A. Belo, H. Sasaki, J. Nakai, B. Dworniczak, B.E. Ehrlich, P. Pennekamp, and H. Hamada. (2012). Cilia at the node of mouse embryos sense fluid flow for left-right determination via Pkd2. Science 338: 226-231.

Yu, Y., M.H. Ulbrich, M.H. Li, Z. Buraei, X.Z. Chen, A.C. Ong, L. Tong, E.Y. Isacoff, and J. Yang. (2009). Structural and molecular basis of the assembly of the TRPP2/PKD1 complex. Proc. Natl. Acad. Sci. USA 106: 11558-11563.

Yuasa, T., A. Takakura, B.M. Denker, B. Venugopal, and J. Zhou. (2004). Polycystin-1L2 is a novel G-protein-binding protein. Genomics 84: 126-138.

Zhang, C., B. Balbo, M. Ma, J. Zhao, X. Tian, Y. Kluger, and S. Somlo. (2021). Cyclin-Dependent Kinase 1 Activity Is a Driver of Cyst Growth in Polycystic Kidney Disease. J Am Soc Nephrol 32: 41-51.

Zhu, J., Y. Yu, M.H. Ulbrich, M.H. Li, E.Y. Isacoff, B. Honig, and J. Yang. (2011). Structural model of the TRPP2/PKD1 C-terminal coiled-coil complex produced by a combined computational and experimental approach. Proc. Natl. Acad. Sci. USA 108: 10133-10138.


TC#NameOrganismal TypeExample

Polycystin 1 (PKD1 or PC1) assembles with TRPP2 (Q86VP3) in a stoichiometry of 3TRPP2: 1PKD1, forming the receptor/ion channel complex (Yu et al., 2009). The C-terminal coiled-coil complex is critical for proper assembly (Zhu et al., 2011).  Missense mutations have been identified that affect membrane topogenesis (Nims et al. 2011). Biomarkers for polycystic kidney diseases have been identified (Hogan et al. 2015).  Extracellular divalent ions, including Ca2+, inhibit permeation of monovalent ions by directly blocking the TRPP2 channel pore. D643, a negatively charged amino acid in the pore, is crucial for channel permeability (Arif Pavel et al. 2016). Polycystin (TRPP/PKD) complexes, made of transient receptor potential channel polycystin (TRPP)4 and polycystic kidney disease (PKD) proteins, play key roles in coupling extracellular stimuli with intracellular Ca2+ signals. PKD1 and PKD2 form a complex, the structure of which has been solved in 3-dimensions at high resolution.  The complex consists of PKD1:PKD2 = 3:1. PKD1 consists of a voltage-gated ion channel fold that interacts with PKD2 to complete a domain-swapped TRP architecture with unique features (Su et al. 2018; Su et al. 2018). The C-terminal tail of PKD1 may play a role in the prognosis of renal disease (Higashihara et al. 2018). TRPP2 uses 2 gating charges found in its fourth TMS (S4) to control its conductive state (Ng et al. 2019). Rosetta structural predictions demonstrated that the S4 undergoes approximately 3- to 5-Å transitional and lateral movements during depolarization coupled to opening of the channel pore. Both gating charges form state-dependent cation-pi interactions within the voltage sensor domain (VSD) during membrane depolarization. The transfer of a single gating charge per channel subunit is required for voltage, temperature, and osmotic swell polymodal gating. Thus, TRPP2 channel opening is dependent on activation of its VSDs (Ng et al. 2019).  Polycystin-1 assembles with Kv channels to govern cardiomyocyte repolarization and contractility (Altamirano et al. 2019). Three-dimensional in vitro models answer questions about ADPKD cystogenesis (Dixon and Woodward 2018). The polycystin-1 subunit directly contributes to the channel pore, and its eleven TMSs are sufficient for its channel function (Wang et al. 2019).  Polycystin-1 inhibits cell proliferation through phosphatase PP2A/B56alpha (Tang et al. 2019). Polycystin-1 regulates cardiomyocyte mitophagy (Ramírez-Sagredo et al. 2021). Maser and Calvet 2020 reviewed structural and functional features shared by polycystin-1 and the adhesion GPCRs (TC# 9.A.14.6.2) and discussed the implications of such similarities for our understanding of the functions of these proteins. Mutations in PKD1 and PKD2 cause autosomal dominant polycystic kidney disease (ADPKD). Polycystins are expressed in the primary cilium, and disrupting cilia structure slows ADPKD progression following inactivation of polycystins. Dysregulation of cyclin-dependent kinase 1 (Cdk1) is an early driver of cyst cell proliferation in ADPKD due to Pkd1 inactivation (Zhang et al. 2021). Genetic removal of c-Jun N-terminal kinases, Jnk1 and Jnk2, suppresses the nuclear accumulation of phospho c-Jun, reduces proliferation and reduces the severity of cystic disease. While Jnk1 and Jnk2 are thought to have largely overlapping functions, Jnk1 loss is nearly as effective as the double loss of Jnk1 and Jnk2 (Smith et al. 2021). Polycystic kidney disease (PKD), comprising autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD), is characterized by incessant cyst formation in the kidney and liver. ADPKD and ARPKD represent the leading genetic causes of renal disease in adults and children, respectively. ADPKD is caused by mutations in PKD1 encoding polycystin1 (PC1) and PKD2 encoding polycystin 2 (PC2). PC1/2 are multi-pass transmembrane proteins that form a complex localized in the primary cilium. Predominant ARPKD cases are caused by mutations in polycystic kidney (Ma 2021). The mechanism of tethered agonist-mediated signaling by polycystin-1 has been investigated (Pawnikar et al. 2022). PC1 is an 11 TMS protein encoded by the PKD1 gene. It has a complex posttranslational maturation process, with over five proteolytic cleavages, and is found at multiple cellular locations. The initial description of the binding and activation of heterotrimeric Galphai/o by the juxtamembrane region of the PC1 cytosolic C-terminal tail (C-tail) opened the door tothe possibility of potential functions as a novel G protein-coupled receptor (GPCR). Subsequent  assays supported an ability of the PC1 C-tail to bind numerous members of the Galpha protein family and to either inhibit or activate G protein-dependent pathways involved in the regulation of ion channel activity, transcription factor activation, and apoptosis. PC1-mediated G protein regulation prevents kidney cyst development. Similarities between PC1 and the adhesion class of 7-TMS GPCRs, most notably a conserved GPCR proteolysis site (GPS) before the first TM domain, which undergoes autocatalyzed proteolytic cleavage, suggest potential mechanisms for PC1-mediated regulation of G protein signaling.  reviewed the evidence supporting GPCR-like functions of PC1 and their relevance to cystic disease, discusses the involvement of GPS cleavage and potential ligands in regulating PC1 GPCR function, and explores potential connections between PC1 GPCR-like activity and regulation of the channel properties of the polycystin receptor-channel complex (Maser et al. 2022).


Polycystin 1 of Homo sapiens


Polycystic kidney disease protein 1-like 3 (PC1-like 3 protein or PKD1L3) (Polycystin-1L3).  May particpate in formation of the TRP sour taste receptor (see 1.A.5.2.2) (Ishimaru et al. 2010). Mediates Ca2+ influx-operated Ca2+ entry that generates pronounced Ca2+ spikes. Triggered by rapid onset/offset of Ca2+, voltage, or acid stimuli, Ca2+-dependent activation amplifies a small Ca2+ influx via the channel which concurrently drives self-limiting negative feedback inactivation that is regulated by the Ca2+-binding EF hands of its partner protein, PKD2-L1 (Hu et al. 2015). Polycystin-1 inhibits eIF2alpha phosphorylation and cell apoptosis through a PKR-eIF2alpha pathway (Tang et al. 2017).


PKD1L3 of Homo sapiens


Heteromeric polycystic kidney disease proteins 1 and 2-like 1 (PKD1L1/PKD2L1) cation (calcium) channel of kidney primary cilia (DeCaen et al. 2013).  PKD2L1 is probably orthologous to mouse TC# 1.A.5.2.2. The voltage dependence of PKD2L1 may reflect the charge state of the S4 domain (Numata et al. 2017). PKD2L1, (TRPP3) is involved in the sour sensation and other pH-dependent processes and is a nonselective cation channel that can be regulated by voltage, protons, and calcium. The 3-d structure has been determined by cryoEM at 3.4 Å resolution (Su et al. 2018). Unlike its ortholog PKD2, the pore helix and TMS6, which are involved in upper and lower-gate opening, adopt an open conformation. The pore domain dilation is coupled to conformational changes of voltage-sensing domains via a series of pi-pi interactions, suggesting a potential PKD2L1 gating mechanism (Su et al. 2018).



PKD1L1/PKD2L1 of Homo sapiens


One of 10 receptors for the egg jelly ligands (REJ, REJ1 or PKD-REJ1) inducing the acrosome reaction in sea urchin eggs. Could be a regulator of sperm ion channels (Gunaratne et al. 2007).

REJ of Strongylocentrotus purpuratus (Purple sea urchin)


PKD-REJ4 of 2829 aas and 2 TMSs, one N-terminal and one C-terminal (Gunaratne et al. 2007). Shows homology with hydrophilic domains in human PKDs.

REJ4 of Strongylocentrotus purpuratus (Purple sea urchin)


PKD-REJ3 of 2681 aas (Gunaratne et al. 2007). Polycystin-2 (TC# 1.A.5.2.3) associates with the polycystin-1 homolog, suREJ3, and localizes to the acrosomal region of sea urchin spermatozoa (Neill et al. 2004).

REJ3 of Strongylocentrotus purpuratus (Purple sea urchin)


Polycystin-1L2 G-protein receptor of 2459 aas and about 18 TMSs in a 1 (N-terminal) + 6-8 + 3 + 7 ( C-terminal) TMS arrangement.  It probably functions as an ion-channel regulator as well as a G-protein-coupled receptor (Yuasa et al. 2004).

Polycystin-1L2 of Homo sapiens


TC#NameOrganismal TypeExample

Polycystin 2 (PKD2, PC2 or TRPP2) of 968 aas and 8 or 9 TMSs (Anyatonwu and Ehrlich, 2005). It is regulated by α-actinin (AAC17470) by direct binding, influencing its channel activity (Li et al., 2007), and is also regulated also by diaphanous-related formin 1 (mDia1) (Bai et al., 2008). It has 8 TMSs with 6 TMSs in the channel domain with N- and C- termini inside (Hoffmeister et al., 2010).  PC2 interacts with the inositol 1,4,5-trisphosphate receptor (IP(3)R) to modulate Ca2+ signaling (Li et al. 2009). The PKD2 voltage-sensor domain retains two of four gating charges commonly found in voltage-gated ion channels. The PKD2 ion permeation pathway is constricted at the selectivity filter near the cytoplasmic end of S6, suggesting that two gates regulate ion conduction (Shen et al. 2016). 15% of cases of polycystic kidney disease result from mutations in the gene encoding this protein, while 85% are in PKD1 (Ghata and Cowley 2017). Topological changes between the closed and open sub-conductance states of the functional channel are observed with an inverse correlation between conductance and height of the channel. Intrinsic PC2 mechanosensitivity in response to external forces was also observed (Lal et al. 2018). PC2 is present in ciliary membranes of the kidney and shares a transmembrane fold with other TRP channels as well as an extracellular domain found in TRPP and TRPML channels. Wang et al. 2019 characterized the phosphatidylinositol biphosphate (PIP2) and cholesterol interactions with PC2. PC2 has  a PIP binding site close to the equivalent vanilloid/lipid binding site in the TRPV1 channel and a binding site for cholesterol. The two classes of lipid binding sites were compared with sites observed in other TRPs and in Kv channels, suggesting that PC2, in common with other ion channels, may be modulated by both PIPs and cholesterol (Wang et al. 2019). Genetic removal of c-Jun N-terminal kinases, Jnk1 and Jnk2, suppresses the nuclear accumulation of phospho c-Jun, reduces proliferation and reduces the severity of cystic disease. While Jnk1 and Jnk2 are thought to have largely overlapping functions, Jnk1 loss is nearly as effective as the double loss of Jnk1 and Jnk2 (Smith et al. 2021). Polycystin-2 (TRPP2): ion channel properties and regulation have been described (Del Rocío Cantero and Cantiello 2022). Regulation of the PKD2 channel by TACAN (TC# 1.A.119.1.2) has been described (Liu et al. 2022). The mouse ortholog is 90% identical to the human protein.


Polycystin 2 of Homo sapiens (Q13563)


Polycystic kidney disease Z-like protein, TrpP3 or PKD2L1 (50% identical to Polycystin 2 (1.A.5.2.1); regulated by α-actinin (AAC17470) by direct binding; Li et al, 2007). May form a heterodimeric complex with PKD1L3 (1.A.5.1.2) to form the TRP sour taste channel receptor (Ishimaru et al., 2006; Ishimaru et al. 2010).  Polycystic kidney disease (PKD) protein 2 Like 1 (PKD2L1) is also called transient receptor potential polycystin-3 (TRPP3).  It regulates Ca2+-dependent hedgehog signalling in primary cilia, intestinal development and sour taste. Two intra-membrane residues, aspartic acid 349 (D349) and glutamic acid 356 (E356) in the third TMS are critical for PKD2L1 channel function which may itself sense acids (Hussein et al. 2015). Extracellular loops are involved in assemby of the complex (Salehi-Najafabadi et al. 2017). It Component of a heteromeric calcium-permeable ion channel formed by PKD1 and PKD2 that is activated by interaction between PKD1 and a Wnt family member, such as WNT3A and WNT9B. Can also form a functional, homotetrameric ion channel (PubMed:27214281). It functions as a cation channel involved in fluid-flow mechanosensation by the primary cilium in the renal epithelium (Nauli et al. 2003). It functions as outward-rectifying K+ channel, but is also permeable to Ca2+, and to a much lesser degree, to Na+ (Kleene and Kleene 2017). It
may contribute to the release of Ca2+ stores from the endoplasmic reticulum. Together with TRPV4, it forms mechano- and thermosensitive channels in cilia (Köttgen et al. 2008). The
PKD1 channel protein.  It is involved in left-right axis specification via its role in sensing nodal flow; forms a complex with PKD1L1 in cilia to facilitate flow detection in left-right patterning (Yoshiba et al. 2012 ; Katoh et al. 2023). Detection of asymmetric nodal flow gives rise to a Ca2+ signal that is required for normal, asymmetric expression of genes involved in the specification of body left-right laterality (Yoshiba et al. 2012).


TrpP3 of Mus musculus (Q14B55)


Polycystin-2, PKD2 or PKD-REJ2 of 907 aas and 8 TMSs (Gunaratne et al. 2007). Polycystin-2 associates with the polycystin-1 homolog, suREJ3 (TC# 1.A.5.1.6), and localizes to the acrosomal region of sea urchin spermatozoa (Neill et al. 2004).

REJ2 of Strongylocentrotus purpuratus (Purple sea urchin)


Polycystin-2 (CePc2) (Polycystic kidney disease 2 protein homologue)


Pkd-2 of Caenorhabditis elegans


TC#NameOrganismal TypeExample

The lysosomal monovalent cation/Ca2+ channel, TRP-ML1 (Mucolipin-1) (associated with the human lipid storage disorder, mucolipidosis type IV (MLIV)) (Kiselyov et al., 2005; Luzio et al., 2007). TRPML1 is an endolysosomal iron release channel (Dong et al., 2008).  It interacts with TMEM163, a CDF heavy metal transporter (TC# 2.A.4.8.3).  Together these proteins function in Zn2+ homeostasis, possibly by exporting Zn2+ (Cuajungco et al. 2014).  The MLIV disease could result from Zn2+ overload.  TrpML1 is probably involved in Zn2+ uptake into lysosomes (Cuajungco and Kiselyov 2017). Asp residues within the luminal pore may control calcium/pH regulation. A synthetic agonist, ML-SA1, can bind to the pore region to force a direct dilation of the lower gate (Schmiege et al. 2018). This channel plays a role in vesicle contraction following phagocytosis or pinocytosis, allowing maintenance of cell volume (Freeman et al. 2020). A mutation gave rise to progressive psychomotor delay, and atrophy of the corpus callosum and cerebellum was observed on brain magnetic resonance images (Hayashi et al. 2020).


TRP-ML1 (Mucolipin-1) of Homo sapiens (Q9GZU1)


The TRP-ML3 or TRPML3 or Mcoln3 (Mucolipin-3) inward rectifying cation channel; associated with the mouse Viartini-Waddler phenotype when mutant (A419P) (Kim et al., 2007; Cuajungco and Samie 2008). H+-regulated Ca2+ channel that shuttles between intracellular vesicular compartments and the plasma membrane (Kim et al., 2010).


Trp-ML3 of Mus musculus


Mucolipin-2 (TRPML2) non-selective plasma membrane cation channel (Ca2+ permeable). Shows inward rectification like TRPML1 and TRPML3 (Lev et al., 2010). Induces cell degeneration. Causes embryonic lethality, pigmentation defects and deafness, and regulates the acidification of early endosomes (Noben-Trauth, 2011). Found in the plasma membrane and early- and late-endosomes as well as lysosomes.  Activated by a transient reduction of extracellular sodium followed by sodium replenishment, by small chemicals related to sulfonamides, and by PI(3,5)P2, a rare phosphoinositide that naturally accumulates in the membranes of endosomes and lysosomes, and thus could act as a physiologically relevant agonist (García-Añoveros and Wiwatpanit 2014).  TRPML2 can form heteromultimers with TRPML1 and TRPML3; in B-lymphocytes, TRPML2 and TRPML1 may play redundant roles.  TRPML2 may play a role in immune cell development and inflammatory responses (Cuajungco et al. 2015). The TRPML family hallmark is a large extracytosolic/lumenal domain (ELD) between TMSs S1 and S2. Viet et al. 2019 presented crystal structures of the tetrameric human TRPML2 ELD. The structures reveal structural responses to the conditions the TRPML2 ELD encounters as the channel traffics through the endolysosomal system.


TRPML2 of Homo sapiens (Q8IZK6)


Mucolipin-3 (Mcoln3, TRPML3). Orthologue of 1.A.5.3.2.  Asp residues within the luminal pores of all mucolipins may function to control calcium/pH regulation. A synthetic agonist, ML-SA1, can bind to the pore region of TRPMLs to force a direct dilation of the lower gate. These proteins have multiple ligand binding sites (Schmiege et al. 2018).

TRPML3 of Homo sapiens


Mucolipin of 496 aas and 7 TMSs in a 1 + 6 TMS arrangement.  There is a ~200 aa loop between TMSs 1 and 2, and TMS 1 may be a leader sequence.

Mucolipin of Trypanosoma grayi


Uncharacterized protein of 1844 aas and 5 - 6 TMSs. 

UP of Leishmania major


Mucolipin-1 or CUP-5 of 611 aas and 6 TMSs in a 1 + 5 TMS arrangement. This C. elegans ortholog of the human protein is required for lysosome biogenesis. Mutations in cup-5 result in the accumulation of large vacuoles in several cells, in increased cell death, and in embryonic lethality (Treusch et al. 2004).

CUP-5 of Caenorhabditis elegans


TC#NameOrganismal TypeExample
1.A.5.4.1The algal PDK2 cation channel in Chlamydomonas reinhardii, involved in coupling flagellar adhesion at the beginning of mating to the increase in flagellar calcium required for subsequent steps in mating (Huang et al., 2007). (Residues 1278-1346 (the PKD domain) are 25% identical, 54% similar to residues 107-176 in CcaA (TC# 1.A.1.14.2)) AlgaePDK2 of Chlamydomonas reinhardii (A9LE42)