Cystic fibrosis transmembrane conductance regulator: a chloride channel gated by ATP binding and hydrolysis

( views:57, downloads:0 )
Author:
BOMPADRE Silvia G.()
HWANG Tzyh-Chang()
Journal Title:
ACTA PHYSIOLOGICA SINICA
Issue:
Volume 59, Issue 04, 2007
DOI:
Key Word:
ATP-binding cassette transporter;ion channel gating;cystic fibrosis;electrophysiology

Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that belongs to the ATP-binding cassette (ABC) transporter superfamily. Defective function of CFTR is responsible for cystic fibrosis (CF), the most common lethal autosomal recessive disorder in Caucasian populations. The disease is manifested in defective chloride transport across the epithelial cells in various tissues. To date, more than 1400 different mutations have been identified as CF-associated. CFTR is regulated by phosphorylation in its regulatory (R) domain, and gated by ATP binding and hydrolysis at its two nucleotide-binding domains (NBD1 and NBD2). Recent studies reveal that the NBDs of CFTR may dimerize as observed in other ABC proteins. Upon dimerization of CFTR's two NBDs, in a head-to-tail configuration, the two ATP-binding pockets (ABP1 and ABP2) are formed by the canonical Walker A and B motifs from one NBD and the signature sequence from the partner NBD. Mutations of the amino acids that interact with ATP reveal that the two ABPs play distinct roles in controlling ATP-dependent gating of CFTR. It was proposed that binding of ATP to the ABP2, which is formed by the Walker A and B in NBD2 and the signature sequence in NBD1, is critical for catalyzing channel opening. While binding of ATP to the ABP1 alone may not increase the opening rate, it does contribute to the stabilization of the open channel conformation. Several disease-associated mutations of the CFTR channel are characterized by gating defects. Understanding how CFTR's two NBDs work together to gate the channel could provide considerable mechanistic information for future pharmacological studies, which could pave the way for tailored drug design for therapeutical interventions in CF.

  • [1]Riordan,JR,Rommens JM,Kerem BS,Alon N,Rozmahel R,Grzelzak Z,Zielenski J,Lok S,Plavsic N,Chou JL,Drumm ML,Ianuzzi MC,Collins FS,Tsui LC.Identification of the cystic fibrosis gene:cloning and characterization of complementary DNA.Science 1989; 245:1066-1072.
  • [2]Welsh MJ,Smith AE.Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis.Cell 1993; 73:1251-1254.
  • [3]Tsui LC,Durie P.Genotype and phenotype in cystic fibrosis.Hosp Pract 1997; 32:115-118,123-129,134.
  • [4]Quinton PM.Cystic fibrosis:a disease in electrolyte transport.FASEB J 1990; 4:2709-2717.
  • [5]Higgins CF,Linton KJ.The ATP switch model for ABC transporters.Nat Struct Mol Biol 2004; 11:918-926.
  • [6]Knowles MR,Stutts MJ,Spock A,Fischer N,Gatzy JT,Boucher RC.Abnormal ion permeation through cystic fibrosis respiratory epithelium.Science 1983; 221:1067-1070.
  • [7]Boucher RC,Stutts MJ,Knowles MR,Cantley L,Gatzy JT.Na+ transport in cystic fibrosis respiratory epithelia.Abnormal basal rate and response to adenylate cyclase activation.J Clin Invest 1986; 78(5):1245-1252.
  • [8]Anderson MP,Gregory RJ,Thompson S,Souza DW,Paul S,Mulligan RC,Smith AE,Welsh MJ.Demonstration that CFTR is a chloride channel by alteration of its anion selectivity.Science 1991; 253:202-205.
  • [9]Anderson MP,Berger HA,Rich DP,Gregory RJ,Smith AE,Welsh MJ.Nucleoside triphosphates are required to open the CFTR chloride channel.Cell 1991; 67:775-784.
  • [10]Rich DP,Gregory RJ,Anderson MP,Manavalan P,Smith AE,Welsh MJ.Effect of deleting the R domain on CFTR-generated chloride channels.Science 1991; 253:205-207.
  • [11]Bear CE,Duguay F,Naismith AL,Kartner N,Hanrahan JW,Riordan JR.Cl-channel activity in Xenopus oocytes expressing the cystic fibrosis gene.J Biol Chem 1991; 266:19142-19145.
  • [12]Tabcharani JA,Chang XB,Riordan JR,Hartshorn MJ.Phosphorylation-regulated Cl-channel in CHO cells stably expressing the cystic fibrosis gene.Nature 1991; 352:628-631.
  • [13]Bear CE,Li CH,Kartner N,Bridges RJ,Jensen TJ,Ramjeesingh M,Riordan JR.Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR).Cell 1992; 68:809-818.
  • [14]Schwiebert EM,Benos DJ,Egan ME,Stutts MJ,Guggino WB.CFTR is a conductance regulator as well as a chloride channel.Physiol Rev 1999; 79:S145-S163.
  • [15]Gray MA.Bicarbonate secretion:it takes two to tango.Nat Cell Biol 2004; 6(4):292-294.
  • [16]Ko SB,Zeng W,Dorwart MR,Luo X,Kim KH,Millen L,Goto H,Naruse S,Soyombo A,Thomas PJ,Muallem S.Gating of CFTR by the STAS domain of SLC26 transporters.Nat Cell Biol 2004; 6(4):343-350.
  • [17]Nagel G,Hwang TC,Nastiuk KL,Nairn AC,Gadsby DC.The protein kinase A-regulated cardiac Cl-channel resembles the cystic fibrosis transmembrane conductance regulator.Nature 1992; 360(6399):81-84.
  • [18]Csanády L,Chan KW,Seto-Young D,Kopsco DC,Nairn AC,Gadsby DC.Severed channels probe regulation of gating of cystic fibrosis transmembrane conductance regulator by its cytoplasmic domains.J Gen Physiol 2000; 116:477-500.
  • [19]Bompadre SG,Ai T,Cho JH,Wang X,Sohma Y,Li M,Hwang TC.CFTR gating I:Characterization of the ATP-dependent gating of a phosphorylation-independent CFTR channel (△R-CFTR).J Gen Physiol 2005; 125:361-375.
  • [20]Gadsby DC,Nairn AC.Control of CFTR channel gating by phosphorylation and nucleotide hydrolysis.Physiol Rev 1999;79:S77-S107.
  • [21]Zhou Z,Hwang TC.Gating of the cystic fibrosis transmembrane regulator (CFTR) chloride channels.In:Advances in Molecular Biology,38.Bittar EE.ed.Elsevier,2007,145-180.
  • [22]Gadsby DC,Nagel G,Hwang TC.The CFTR chloride channel of mammalian heart.Annu Rev Physiol 1995; 57:387-416.
  • [23]Hwang TC,Nagel G,Nairn AC,Gadsby DC.Regulation of the gating of cystic fibrosis transmembrane conductance regulator Cl channels by phosphorylation and ATP hydrolysis.Proc Natl Acad Sci USA 1994; 91:4698-4702.
  • [24]Gunderson KL,Kopito RR.Effects of pyrophosphate and nucleotide analogs suggest a role for ATP hydrolysis in cystic fibrosis transmembrane regulator channel gating.J Biol Chem 1994; 269:19349-19353.
  • [25]Carson MR,Travis SM,Welsh MJ.The two nucleotide-binding domains of cystic fibrosis transmembrane conductance regulator (CFTR) have distinct functions in controlling channel activity.J Biol Chem 1995; 270:1711-1717.
  • [26]Azzaria M,Schurr E,Gros P.Discrete mutations introduced in the predicted nucleotide-binding sites of the mdr1 gene abolish its ability to confer multidrug resistance.Mol Cell Biol 1989; 9(12):5289-5297.
  • [27]Gunderson KL,Kopito RR.Conformational states of CFTR associated with channel gating:the role ATP binding and hydrolysis.Cell 1995; 82:231-239.
  • [28]Ramjeesingh M,Li C,Garami E,Huan LJ,Galley K,Wang Y,Bear CE.Walker mutations reveal loose relationship between catalytic and channel-gating activities of purified CFTR (cystic fibrosis transmembrane conductance regulator).Biochemistry 1999; 38:1463-1468.
  • [29]Szabo K,Szakacs G,Hegeds T,Sarkadi B.Nucleotide occlusion in the human cystic fibrosis transmembrane conductance regulator.Different patterns in the two nucleotide binding domains.J Biol Chem 1999; 274:12209-12212.
  • [30]Aleksandrov L,Aleksandrov AA,Chang XB,Riordan JR.The first nucleotide binding domain of cystic fibrosis transmembrane conductance regulator is a site of stable nucleotide interaction,whereas the second is a site of rapid turnover.J Biol Chem 2002;277:15419-15425.
  • [31]Basso C,Vergani P,Nairn AC,Gadsby DC.Prolonged nonhydrolytic interaction of nucleotide with CFTR's NH2terminal nucleotide binding domain and its role in channel gating.J Gen Physiol 2003; 122:333-348.
  • [32]Lewis HA,Buchanan SG,Burley SK,Conners K,Dickey M,Dorwart M,Fowler R,Gao X,Guggino WB,Hendrickson WA,Hunt JF,Kearins MC,Lorimer D,Maloney PC,Post KW,Rajashankar KR,Rutter ME,Sauder JM,Shriver S,Thibodeau PH,Thomas PJ,Zhang M,Zhao X,Emtage S.Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator.EMBO J 2004; 23:282-293.
  • [33]Lewis HA,Zhao X,Wang C,Sauder JM,Rooney I,Noland BW,Lorimer D,Kearins MC,Conners K,Condon B,Maloney PC,Guggino WB,Hunt JF,Emtage S.Impact of the deltaFS08 mutation in first nucleotide-binding domain of human cystic fibrosis transmembrane conductance regulator on domain folding and structure.J Biol Chem 2005; 280:1346-1353.
  • [34]Anderson MP,Welsh MJ.Regulation by ATP and ADP of CFTR chloride channels that contain mutant nucleotide-binding domains.Science 1992; 257:1701-1704.
  • [35]Winter MC,Sheppard DN,Carson MR,Welsh MJ.Effect of ATP concentration on CFTR Cl-channels:A kinetic analysis of channel regulation.Biophys J 1994; 66:1398-1403.
  • [36]Schultz BD,Venglarik CJ,Bridges RJ,Frizzell RA.Regulation of CFTR Cl-channel gating by ADP and ATP analogues.J Gen Physiol 1995; 105:329-361.
  • [37]Weinreich F,Riordan JR,Nagel G.Dual effects of ADP and adenylylimidodiphosphate on CFTR channel kinetics show binding to two different nucleotide binding sites.J Gen Physiol 1999;114:55-70.
  • [38]Bompadre SG,Cho JH,Wang X,Zou X,Sohma Y,Li M,Hwang TC.CFTR gating Ⅱ:Effects of nucleotide binding on the stability of open states.J Gen Physiol 2005; 125:377-394.
  • [39]Hopfner KP,Karcher A,Shin DS,Craig L,Arthur LM,Carney JP,Tainer JA.Structural biology of Rad50 ATPase:ATP-driven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily.Cell 2000; 101:789-800.
  • [40]Smith PC,Karpowich N,Millen L,Moody JE,Rosen J,Thomas PJ,Hunt JF.ATP binding to the motor domain from an ABC transporter drives formation of a nucleotide sandwich dimer.Mol Cell 2002; 10:139-149.
  • [41]Chen J,Lu G,Lin J,Davidson AL,Quiocho FA.A tweezers-like motion of the ATP-binding cassette dimer in an ABC transport cycle.Mol Cell 2003; 12:651-661.
  • [42]Zaitseva J,Jenewein S,Wiedenmann A,Benabdelhak H,Holland IB,Schmitt L.Functional characterization and ATP-induced dimerization of the isolated ABC-domain of the haemolysin B transporter.Biochemistry 2005; 44:9680-9690.
  • [43]Locher KP,Lee AT,Rees DC.The E.coli BtuCD structure:a framework for ABC transporter architecture and mechanism.Science 2002; 296:1091-1098.
  • [44]Dawson RJ,Locher KP.Structure of a bacterial multidrug ABC transporter.Nature 2006; 443:180-185.
  • [45]Hung LW,Wang IX,Nikaido K,Liu PQ,Ames GFL,Kim SH.Crystal structure of the ATP-binding subunit of an ABC transporter.Nature 1998; 396:703-707.
  • [46]Moody JE,Millen L,Binns D,Hunt JF,Thomas PJ.Cooperative,ATP-dependent association of the nucleotide binding cassettes during the catalytic cycle of ATP-binding cassette transporters.J Biol Chem 2002; 277:21111-21114.
  • [47]Rosenberg MF,Kamis AB,Aleksandrov LA,Ford RC,Riordan JR.Purification and crystallization of the cystic fibrosis transmembrane conductance regulator (CFTR).J Biol Chem 2004;279:39051-39057.
  • [48]Csanady L,Chan KW,Nairn AC,Gadsby DC.Functional roles of nonconserved structural segments in CFTR's NH2-terminal nucleotide binding domain.J Gen Physiol 2005; 125:43-55.
  • [49]Sauna ZE,Muller M,Peng XH,Ambudkar SV.Importance of the conserved Walker B glutamate residues,556 and 1201,for the completion of the catalytic cycle of ATP hydrolysis by human P-glycoprotein (ABCB1).Biochemistry 2002; 41(47):13989-14000.
  • [50]Carrier I,Julien M,Gros P.Analysis of catalytic carboxylate mutants E552Q and E1197Q suggests asymmetric ATP hydrolysis by the two nucleotide-binding domains of P-glycoprotein.Biochemistry 2003; 42(44):12875-12885.
  • [51]Powe AC Jr,Al-Nakkash L,Li M,Hwang TC.Mutation of Walker-A lysine 464 in cystic fibrosis transmembrane conductance regulator reveals functional interaction between its nucleotide-binding domains.J Physiol 2002; 539:333-346.
  • [52]Vergani P,Nairn AC,Gadsby DC.On the mechanism of MgATPdependent gating of CFTR Cl-channels.J Gen Physiol 2003; 121:17-36.
  • [53]Vergani P,Lockless SW,Nairn AC,Gadsby DC.CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains.Nature 2005; 433:876-880.
  • [54]Mense M,Vergani P,White DM,Altberg G,Nairn AC,Gadsby DC.In vivo phosphorylation of CFTR promotes formation of a nucleotide-binding domain heterodimer.EMBO J 2006; 25:4728-4739.
  • [55]Bompadre SG,Sohma Y,Li M,Hwang TC.G551D and G1349D,two CF-associated mutations in the signature sequence of CFTR,exhibit distinct gating defects.J Gen Physiol 2007; 129:285-298.
  • [56]Zhou Z,Wang X,Liu H,Zou X,Li M,Hwang TC.The two ATP binding sites of CFTR play distinct roles in gating kinetics and energetics.J Gen Physiol 2006; 128:413-422.
  • [57]Aleksandrov L,Mengos A,Chang XB,Aleksandrov A,Riordan JR.Differential interactions of nucleotides at the two nucleotide binding domains of CFTR.J Biol Chem 2001; 276:12918-12923.
  • [58]Zhou Z,Wang X,Li M,Sohma Y,Zou X,Hwang TC.High affinity ATP/ADP analogues as new tools for studying CFTR gating.J Physiol 2005; 569:447-457.
  • [59]Berger AL,Ikuma M,Welsh MJ.Normal gating of CFTR requires ATP binding to both nucleotide-binding domains and hydrolysis at the second nucleotide-binding domain.Proc Natl Acad Sci USA 2005; 102:455-460.
  • [60]Gillespie PG,Gillespie SK,Mercer JA,Shah K,Shokat KM.Engineering of the myosin-ibeta nucleotide-binding pocket to create selective sensitivity to N(6)-modified ADP analogs.J Biol Chem 1999; 274:31373-31381.
  • [61]Drumm ML,Wilkinson DJ,Smit LS,Worrell RT,Strong TV,Frizzell RA,Dawson DC,Collins FS.Chloride conductance expressed by delta F508 and other mutant CFTRs in Xenopus oocytes.Science 1991; 254:1797-1799.
  • [62]Cai Z,Taddei A,Sheppard DN.Differential sensitivity of the cystic fibrosis (CF)-associated mutants G551D and G1349D to potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl-channel.J Biol Chem 2006; 281:1970-1977.
  • [63]Cutting GR,Kasch LM,Rosenstein BJ,Zielenski J,Tsui LC,Antonarakis SE,Kazazian HH Jr.A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein.Nature 1990; 346:366-369.
  • [64]Kerem BS,Zielenski J,Markiewicz D,Bozon D,Gazit E,Yahav J,Kennedy D,Riordan JR,Collins FS,Rommens JM,Tsui LC.Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene.Proc Natl Acad Sci USA 1990; 87:8447-8451.
  • [65]Salvatore F,Scudiero O,Castaldo G.Genotype-phenotype correlation in cystic fibrosis:the role of modifier genes.Am J Med Genet 2002; 111:88-95.
  • [66]Bompadre SG,Li M,Hwang TC.G551D,a mutation in the signature sequence of CFTR,abolishes ATP-dependent increase of the opening rate.Biophy J 2007; 277a (Suppl):1307-Pos(Abstract).
  • [67]Wang W,Bernard K,Li G,Kirk KL.Curcumin opens cystic fibrosis transmembrane conductance regulator channels by a novel mechanism that requires neither ATP binding nor dimerization of the nucleotide-binding domains.J Biol Chem 2007; 282(7):4533-4544.
  • [68]Schultz BD,Singh AK,Devor DC,Bridges RJ.Pharmacology of CFTR chloride channel activity.Physiol Rev 1999; 79(Suppl):S109-S144.
  • [69]Hwang TC,Sheppard DN.Molecular pharmacology of the CFTR Cl-channel.Trends Pharmacol Sci 1999; 20(11):448-453.
  • [70]Moran O,Galietta LJ,Zegarra-Moran O.Binding site of activators of the cystic fibrosis transmembrane conductance regulator in the nucleotide binding domains.Cell Mol Life Sci 2005; 62(4):446-460.
  • [71]Zegarra-Moran O,Monteverde M,Galietta LJ,Moran O.Functional analysis of mutations in the putative binding site for cystic fibrosis transmembrane conductance regulator potentiators:interaction between activation and inhibition.J Biol Chem 2007;282(12):9098-9104.
WanfangData CO.,Ltd All Rights Reserved
About WanfangData | Contact US
Healthcare Department, Fuxing Road NO.15, Haidian District Beijing, 100038 P.R.China
Tel:+86-010-58882616 Fax:+86-010-58882615 Email:yiyao@wanfangdata.com.cn