The ABC protein turned chloride channel whose failure causes cystic fibrosis

Gadsby, David C.; Vergani, Paola; Csanády, László

doi:10.1038/nature04712

Cited by 616 publications

(717 citation statements)

References 90 publications

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“…The structure of the bacterial Hi-TehA reported by Chen et al (2010) provided a molecular basis to analyze ion transport and selectivity for members of this class of anion channel proteins, which exhibit architecture clearly distinct from those of other known anion channels such as the CLCs, CFTR, or TMEM16A (Dutzler et al, 2002;Gadsby et al, 2006;Caputo et al, 2008;Schroeder et al, 2008;Yang et al, 2008;Zifarelli and Pusch, 2010). This structure guided our functional analysis of the molecular nature of the SLAC/SLAH selectivity filter.…”

Section: Discussionmentioning

confidence: 88%

A Single-Pore Residue Renders the Arabidopsis Root Anion Channel SLAH2 Highly Nitrate Selective

et al. 2014

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In contrast to animal cells, plants use nitrate as a major source of nitrogen. Following the uptake of nitrate, this major macronutrient is fed into the vasculature for long-distance transport. The Arabidopsis thaliana shoot expresses the anion channel SLOW ANION CHANNEL1 (SLAC1) and its homolog SLAC1 HOMOLOGOUS3 (SLAH3), which prefer nitrate as substrate but cannot exclude chloride ions. By contrast, we identified SLAH2 as a nitrate-specific channel that is impermeable for chloride. To understand the molecular basis for nitrate selection in the SLAH2 channel, SLAC1 and SLAH2 were modeled to the structure of HiTehA, a distantly related bacterial member. Structure-guided site-directed mutations converted SLAC1 into a SLAH2-like nitrate-specific anion channel and vice versa. Our findings indicate that two pore-occluding phenylalanines constrict the pore. The selectivity filter of SLAC/SLAH anion channels is determined by the polarity of pore-lining residues located on alpha helix 3. Changing the polar character of a single amino acid side chain (Ser-228) to a nonpolar residue turned the nitrate-selective SLAH2 into a chloride/nitrate-permeable anion channel. Thus, the molecular basis of the anion specificity of SLAC/SLAH anion channels seems to be determined by the presence and constellation of polar side chains that act in concert with the two pore-occluding phenylalanines.

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Section: Discussionmentioning

confidence: 88%

A Single-Pore Residue Renders the Arabidopsis Root Anion Channel SLAH2 Highly Nitrate Selective

et al. 2014

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“…This would be consistent with the idea that activation of CFTR is a two-step process; the first step is controlled by phosphorylation of the regulatory domain, and the second step is controlled by ATP interactions with the NBDs (2, 3, 6, 7). Once the channel has been "activated" it will cycle between the closed and open states because of ATP-dependent channel gating governed by the NBDs (6,7). This gating cycle also appears to involve changes in accessibility to both MTSET and MTSES, at least as reported by a cysteine substituted for Arg-334 (18), although in this case there is no apparent charge dependence of accessibility.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylation of the regulatory domain by cAMP-dependent protein kinase A (PKA) is a prerequisite for channel opening (2,3). Following phosphorylation, channel opening and closing are controlled by ATP interactions with the two intracellular nucleotide binding domains (NBDs) (6,7). How these cytoplasmic processes lead to a structural rearrangement of the TM regions that results in opening of the Cl Ϫ permeation pathway is not known.…”

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confidence: 99%

State-dependent Access of Anions to the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Pore

Fatehi

Linsdell

2008

Journal of Biological Chemistry

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The cystic fibrosis transmembrane conductance regulator (CFTR) Cl ؊ channel is gated by intracellular factors; however, conformational changes in the channel pore associated with channel activation have not been identified. We have used patch clamp recording to investigate the state-dependent accessibility of substituted cysteine residues in the CFTR channel pore to a range of cysteine-reactive reagents applied to the extracellular side of the membrane. Using functional modification of the channel current-voltage relationship as a marker of modification, we find that several positively charged reagents are able to penetrate deeply into the pore from the outside irrespective of whether or not the channels have been activated. In contrast, access of three anionic cysteine-reactive reagents, the methanesulfonate sodium (2-sulfonatoethyl)methanesulfonate, the organic mercurial p-chloromercuriphenylsulfonic acid, and the permeant anion Au(CN) 2 ؊ , to several different sites in the pore is strictly limited prior to channel activation. This suggests that in nonactivated channels some ion selectivity mechanism exists to exclude anions yet permit cations into the channel pore from the extracellular solution. We suggest that activation of CFTR channels involves a conformational change in the pore that removes a strong selectivity against anion entry from the extracellular solution. We propose further that this conformational change occurs in advance of channel opening, suggesting that multiple distinct closed pore conformations exist.

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“…In particular, they will be useful to understand how multi-drug ABC transporters recognize diverse drugs, or how inward-facing conformations of ABC exporters may bind substrates. Eukaryotic ABC transporters are also involved in other processes such as gated chloride flux through CFTR (Sheppard & Welsh 1999;Riordan 2005;Gadsby et al 2006), the regulation of potassium channels by SUR1 (Campbell et al 2003) or the loading of antigenic peptides onto MHC class I molecules by Tap1/2 and tapasin (Abele & Tampe 2004). These processes cannot be modelled readily using bacterial homologues, suggesting that direct structure determination is required to understand their mechanisms.…”

Section: Future Challengesmentioning

confidence: 99%

Structure and mechanism of ATP-binding cassette transporters

Locher

2008

Phil. Trans. R. Soc. B

357

300

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ATP-binding cassette (ABC) transporters constitute a large superfamily of integral membrane proteins that includes both importers and exporters. In recent years, several structures of complete ABC transporters have been determined by X-ray crystallography. These structures suggest a mechanism by which binding and hydrolysis of ATP by the cytoplasmic, nucleotide-binding domains control the conformation of the transmembrane domains and therefore which side of the membrane the translocation pathway is exposed to. A basic, conserved two-state mechanism can explain active transport of both ABC importers and ABC exporters, but various questions remain unresolved. In this article, I will review some of the crystal structures and the mechanistic insight gained from them. Future challenges for a better understanding of the mechanism of ABC transporters will be outlined.

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The ABC protein turned chloride channel whose failure causes cystic fibrosis

Cited by 616 publications

References 90 publications

A Single-Pore Residue Renders the Arabidopsis Root Anion Channel SLAH2 Highly Nitrate Selective

A Single-Pore Residue Renders the Arabidopsis Root Anion Channel SLAH2 Highly Nitrate Selective

State-dependent Access of Anions to the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Pore

Structure and mechanism of ATP-binding cassette transporters

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