The Ion Channel Function of Polycystin-1 in the Polycystin-1/polycystin-2 Complex

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2019 Aug 24

PMID 31441214

Citations 44

Authors

Zhifei Wang

Courtney Ng

Xiong Liu

Yan Wang

Bin Li

Parul Kashyap

Haroon A Chaudhry

Alexis Castro

Enessa M Kalontar

Leah Ilyayev

Rebecca Walker

R Todd Alexander

Feng Qian

Xing-Zhen Chen

Yong Yu

Affiliations

Soon will be listed here.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2 gene, encoding the polycystic kidney disease protein polycystin-1 and the transient receptor potential channel polycystin-2 (also known as TRPP2), respectively. Polycystin-1 and polycystin-2 form a receptor-ion channel complex located in primary cilia. The function of this complex, especially the role of polycystin-1, is largely unknown due to the lack of a reliable functional assay. In this study, we dissect the role of polycystin-1 by directly recording currents mediated by a gain-of-function (GOF) polycystin-1/polycystin-2 channel. Our data show that this channel has distinct properties from that of the homomeric polycystin-2 channel. The polycystin-1 subunit directly contributes to the channel pore, and its eleven transmembrane domains are sufficient for its channel function. We also show that the cleavage of polycystin-1 at the N-terminal G protein-coupled receptor proteolysis site is not required for the activity of the GOF polycystin-1/polycystin-2 channel. These results demonstrate the ion channel function of polycystin-1 in the polycystin-1/polycystin-2 complex, enriching our understanding of this channel and its role in ADPKD.

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References

Su Q, Hu F, Ge X, Lei J, Yu S, Wang T . Structure of the human PKD1-PKD2 complex. Science. 2018; 361(6406). DOI: 10.1126/science.aat9819. View

Vassilev P, Guo L, Chen X, Segal Y, Peng J, Basora N . Polycystin-2 is a novel cation channel implicated in defective intracellular Ca(2+) homeostasis in polycystic kidney disease. Biochem Biophys Res Commun. 2001; 282(1):341-50. DOI: 10.1006/bbrc.2001.4554. View

Parnell S, Magenheimer B, Maser R, Zien C, Frischauf A, Calvet J . Polycystin-1 activation of c-Jun N-terminal kinase and AP-1 is mediated by heterotrimeric G proteins. J Biol Chem. 2002; 277(22):19566-72. DOI: 10.1074/jbc.M201875200. View

Wilkes M, Madej M, Kreuter L, Rhinow D, Heinz V, De Sanctis S . Molecular insights into lipid-assisted Ca regulation of the TRP channel Polycystin-2. Nat Struct Mol Biol. 2017; 24(2):123-130. DOI: 10.1038/nsmb.3357. View

Pavel M, Lv C, Ng C, Yang L, Kashyap P, Lam C . Function and regulation of TRPP2 ion channel revealed by a gain-of-function mutant. Proc Natl Acad Sci U S A. 2016; 113(17):E2363-72. PMC: 4855601. DOI: 10.1073/pnas.1517066113. View

Anyatonwu G, Ehrlich B . Organic cation permeation through the channel formed by polycystin-2. J Biol Chem. 2005; 280(33):29488-93. DOI: 10.1074/jbc.M504359200. View

Mochizuki T, Wu G, Hayashi T, Xenophontos S, Veldhuisen B, Saris J . PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science. 1996; 272(5266):1339-42. DOI: 10.1126/science.272.5266.1339. View

Delmas P, Nomura H, Li X, Lakkis M, Luo Y, Segal Y . Constitutive activation of G-proteins by polycystin-1 is antagonized by polycystin-2. J Biol Chem. 2002; 277(13):11276-83. DOI: 10.1074/jbc.M110483200. View

Su Q, Hu F, Liu Y, Ge X, Mei C, Yu S . Cryo-EM structure of the polycystic kidney disease-like channel PKD2L1. Nat Commun. 2018; 9(1):1192. PMC: 5864754. DOI: 10.1038/s41467-018-03606-0. View

10.

Woodward O, Li Y, Yu S, Greenwell P, Wodarczyk C, Boletta A . Identification of a polycystin-1 cleavage product, P100, that regulates store operated Ca entry through interactions with STIM1. PLoS One. 2010; 5(8):e12305. PMC: 2925899. DOI: 10.1371/journal.pone.0012305. View

11.

Yuan S, Zhao L, Brueckner M, Sun Z . Intraciliary calcium oscillations initiate vertebrate left-right asymmetry. Curr Biol. 2015; 25(5):556-67. PMC: 4469357. DOI: 10.1016/j.cub.2014.12.051. View

12.

Zhou J . Polycystins and primary cilia: primers for cell cycle progression. Annu Rev Physiol. 2009; 71:83-113. DOI: 10.1146/annurev.physiol.70.113006.100621. View

13.

Delmas P . Polycystins: polymodal receptor/ion-channel cellular sensors. Pflugers Arch. 2005; 451(1):264-76. DOI: 10.1007/s00424-005-1431-5. View

14.

Zhu J, Yu Y, Ulbrich M, Li M, Isacoff E, Honig B . Structural model of the TRPP2/PKD1 C-terminal coiled-coil complex produced by a combined computational and experimental approach. Proc Natl Acad Sci U S A. 2011; 108(25):10133-8. PMC: 3121833. DOI: 10.1073/pnas.1017669108. View

15.

Machaca K, HC Hartzell . Reversible Ca gradients between the subplasmalemma and cytosol differentially activate Ca-dependent Cl currents. J Gen Physiol. 1999; 113(2):249-66. PMC: 2223373. DOI: 10.1085/jgp.113.2.249. View

16.

Volynski K, Silva J, Lelianova V, Rahman M, Hopkins C, Ushkaryov Y . Latrophilin fragments behave as independent proteins that associate and signal on binding of LTX(N4C). EMBO J. 2004; 23(22):4423-33. PMC: 526461. DOI: 10.1038/sj.emboj.7600443. View

17.

Chapin H, Caplan M . The cell biology of polycystic kidney disease. J Cell Biol. 2010; 191(4):701-10. PMC: 2983067. DOI: 10.1083/jcb.201006173. View

18.

Grieben M, Pike A, Shintre C, Venturi E, El-Ajouz S, Tessitore A . Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2). Nat Struct Mol Biol. 2016; 24(2):114-122. DOI: 10.1038/nsmb.3343. View

19.

Miledi R . A calcium-dependent transient outward current in Xenopus laevis oocytes. Proc R Soc Lond B Biol Sci. 1982; 215(1201):491-7. DOI: 10.1098/rspb.1982.0056. View

20.

Nauli S, Alenghat F, Luo Y, Williams E, Vassilev P, Li X . Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet. 2003; 33(2):129-37. DOI: 10.1038/ng1076. View