The ABC protein turned chloride channel whose failure causes cystic fibrosis

Laboratory of Cardiac/Membrane Physiology, The Rockefeller University, New York, NY 10021, USA.
Nature (Impact Factor: 41.46). 04/2006; 440(7083):477-83. DOI: 10.1038/nature04712
Source: PubMed


CFTR chloride channels are encoded by the gene mutated in patients with cystic fibrosis. These channels belong to the superfamily of ABC transporter ATPases. ATP-driven conformational changes, which in other ABC proteins fuel uphill substrate transport across cellular membranes, in CFTR open and close a gate to allow transmembrane flow of anions down their electrochemical gradient. New structural and biochemical information from prokaryotic ABC proteins and functional information from CFTR channels has led to a unifying mechanism explaining those ATP-driven conformational changes.

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Article: The ABC protein turned chloride channel whose failure causes cystic fibrosis

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    • "Part of the reason for this uncertainty is the presence of basal ATPase activity of ABC transporters in the absence of substrates, especially in in vitro assays (Woo et al., 2012). In the ATP-dependent anion channel CFTR it has been shown that only one ATP molecule is hydrolyzed by its asymmetric NBD heterodimer per functional cycle (Gadsby et al., 2006). In addition, in human MRP1 (a fused TMD 1 -NBD 1 -TMD 2 -NBD 2 ABC transporter), ATP hydrolysis predominantly occurs in the second NBD (Zhang et al., 2003). "
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    ABSTRACT: ABC transporters form the largest of all transporter families, and their structural study has made tremendous progress over recent years. However, despite such advances, the precise mechanisms that determine the energy-coupling between ATP hydrolysis and the conformational changes following substrate binding remain to be elucidated. Here, we present our thermodynamic analysis for both ABC importers and exporters, and introduce the two new concepts of differential-binding energy and elastic conformational energy into the discussion. We hope that the structural analysis of ABC transporters will henceforth take thermodynamic aspects of transport mechanisms into account as well.
    Protein & Cell 09/2015; DOI:10.1007/s13238-015-0211-z · 3.25 Impact Factor
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    • "The cystic fibrosis transmembrane conductance regulator (CFTR) is located in the apical membrane in various epithelial tissues in the human body, including lungs, the intestinal tract, pancreatic ducts, testes and sweat glands [1]. CFTR is not only responsible for the transport of chloride ions but also acts as a bicarbonate anion and glutathione channel [2] [3]. "
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    ABSTRACT: The cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl(-) channel that is essential for electrolyte and fluid homeostasis. Preliminary evidence indicates that CFTR is a mechanosensitive channel. In lung epithelia, CFTR is exposed to different mechanical forces such as shear stress (Ss) and membrane distention. The present study questioned whether Ss and/or stretch influences CFTR activity (wiltype, ∆F508, G551D). Human CFTR (hCFTR) was heterologously expressed in Xenopus oocytes and the response to the mechanical stimulus and forskolin/IBMX (FI) was measured by two-electrode voltage-clamp experiments. Ss had no influence on hCFTR activity. Injection of an intracellular analogous solution to increase cell volume alone did not affect hCFTR activity. However, hCFTR activity was augmented by injection after pre-stimulation with FI. The response to injection was similar in channels carrying the common mutations ∆F508 and G551D compared to wild type hCFTR. Stretch-induced CFTR activation was further assessed in Ussing chamber measurements using Xenopus lung preparations. Under control conditions increased hydrostatic pressure (HP) decreased the measured ion current including activation of a Cl(-) secretion that was unmasked by the CFTR inhibitor GlyH-101. These data demonstrate activation of CFTR in vitro and in a native pulmonary epithelium in response to mechanical stress. Mechanosensitive regulation of CFTR is highly relevant for pulmonary physiology that relies on ion transport processes facilitated by pulmonary epithelial cells.
    Biochimica et Biophysica Acta 09/2015; 1848(11). DOI:10.1016/j.bbamem.2015.09.009 · 4.66 Impact Factor
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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 mo - lecular nature of the SLAC / SLAH selectivity filter ."
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    ABSTRACT: 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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