CFTR: Break a pump, make a channel

Miller, Christopher

doi:10.1073/pnas.0913576107

Cited by 26 publications

(18 citation statements)

References 9 publications

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“…However, in contrast to current models (5,8,15,16), our direct functional data correlate the open state with an inward facing conformation and the closed state with an outward facing conformation.…”

Section: Discussioncontrasting

confidence: 41%

“…7A, it must be noted that the gates model of Fig. 7B is in direct contradiction of previous suggestions that the CFTR pore should have an atrophied, vestigial inner gate (5,8,15). Our previous work has suggested that the rate of modification by cytoplasmic MTS reagents is independent of channel gating for residues on the cytoplasmic side of the activation gate (red in Fig.…”

Section: Discussioncontrasting

confidence: 41%

“…Ion channels are thought to differ from active transporters in that they have only a single functional gate in the transport pathway, allowing the channel to switch rapidly between "open" (conductive) and "closed" (nonconductive) conformations (5). This has led to the suggestion that CFTR is a "broken pump" that evolved from an actively transporting ABC ancestor due to dysfunction of one of its gates (5,8).…”

mentioning

confidence: 99%

“…Based on the nucleotide binding status of the bacterial templates, it was suggested that the outward facing model of CFTR represents the channel open state, and the inward facing model the closed state (15). Despite a lack of functional evidence and some major inconsistencies with longstanding functional data (see "Discussion"), the idea that CFTR TMDs are outward facing when the channel is open and inward facing when it is closed has been incorporated into recent work on CFTR channel gating (16) and reiterated in reviews of CFTR channel function (5,8). This model has also led to the suggestion that it is the inner (cytoplasmic) gate of CFTR that has been lost functionally (5,8).…”

mentioning

confidence: 99%

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Alternating Access to the Transmembrane Domain of the ATP-binding Cassette Protein Cystic Fibrosis Transmembrane Conductance Regulator (ABCC7)

Wang¹,

Linsdell

2012

Journal of Biological Chemistry

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Background: It is expected that the transport pathway of CFTR should alternate between internally and externally accessible conformations. Results: Access to the channel from both sides of the membrane is regulated by opening and closing. Conclusion:The open state is outwardly facing, the closed state inwardly facing. Significance: These findings prompt reevaluation of prevailing models of CFTR conformational changes.

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Section: Discussioncontrasting

confidence: 41%

Section: Discussioncontrasting

confidence: 41%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Alternating Access to the Transmembrane Domain of the ATP-binding Cassette Protein Cystic Fibrosis Transmembrane Conductance Regulator (ABCC7)

Wang¹,

Linsdell

2012

Journal of Biological Chemistry

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“…Rather, a more common disease mechanism seems to involve destabilizing mutations that impair the correct traffi cking of the functional proteins by enhancing degradation. Cystic fi brosis transmembrane conductance regulator (CFTR), which regulates the anion balance across the plasma membranes of epithelial cells (Miller 2010 ), is an intensely studied model system for membrane protein misfolding diseases. CFTR is composed of 12 TM segments, two nucleotide-binding domains (NBDs) and a regulatory domain.…”

Section: Membrane Protein Misfolding Quality Control and Human Diseasesmentioning

confidence: 99%

Role of Lipids in Folding, Misfolding and Function of Integral Membrane Proteins

Hong

2015

Advances in Experimental Medicine and Biology

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The lipid bilayer that constitutes cell membranes imposes environmental constraints on the structure, folding and function of integral membrane proteins. The cell membrane is an enormously heterogeneous and dynamic system in its chemical composition and associated physical forces. The lipid compositions of cell membranes not only vary over the tree of life but also differ by subcellular compartments within the same organism. Even in the same subcellular compartment, the membrane composition shows strong temporal and spatial dependence on the environmental or biological cues. Hence, one may expect that the membrane protein conformations and their equilibria strongly depend on the physicochemical variables of the lipid bilayer. Contrary to this expectation, the structures of homologous membrane proteins belonging to the same family but from evolutionary distant organisms exhibit a striking similarity. Furthermore, the atomic structures of the same protein in different lipid environments are also very similar. This suggests that certain stable folds optimized for a specific function have been selected by evolution. On the other hand, there is growing evidence that, despite the overall stability of the protein folds, functions of certain membrane proteins require a particular lipid composition in the bulk bilayer or binding of specific lipid species. Here I discuss the specific and nonspecific modulation of folding, misfolding and function of membrane proteins by lipids and introduce several diseases that are caused by misfolding of membrane proteins.

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Ion Channels

Lipscombe

Toro

2013

Encyclopedia of Life Sciences

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Ion channels are membrane proteins that create specialised routes for ions to cross cell membrane lipid bilayers selectively, and at relatively high speeds. All cells of all organisms use ion channels of different types to control a range of functions. The majority of electrical membrane signals originate from the flow of select types of ions through ion channels. Cellular control of ion channel activity is critical for single‐cell and multicellular organisms to respond to their environments. Avoiding external threats, seeking nutrients, adapting to normal developmental processes, creating memories and modifying outputs according to previous events all involve ion channel activity. Ion channel dysfunction underlies multiple human disorders and diseases. Developmental disorders, pain syndromes that include extreme pain as well as congenital indifference to pain, certain types of migraines, epilepsies, ataxias, paralyses, cardiac arrhythmias and renal failure can all be due to malfunctioning ion channels. Thus, ion channels are critically important drug targets for the treatment of many illnesses and disorders. Key Concepts: Ion channels are found in all living cells. Ion channels create specialised routes for ions to cross biological cell membranes. Ion channels support the rapid flow of ions across biological membranes to generate electrical membrane signalling. Ion channels are gated (opened and closed) by a wide range of biological signals. Ion channels are selectively permeable to specific ions. Certain ion channels control the influx of calcium, a critical intracellular second messenger. A range of extracellular, intracellular and membrane signals alter the activity of ion channels. Abnormal ion channel function underlies many disorders and diseases. Ion channels are important targets of drugs and toxins.

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CFTR: Break a pump, make a channel

Cited by 26 publications

References 9 publications

Alternating Access to the Transmembrane Domain of the ATP-binding Cassette Protein Cystic Fibrosis Transmembrane Conductance Regulator (ABCC7)

Alternating Access to the Transmembrane Domain of the ATP-binding Cassette Protein Cystic Fibrosis Transmembrane Conductance Regulator (ABCC7)

Role of Lipids in Folding, Misfolding and Function of Integral Membrane Proteins

Ion Channels

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