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An ion channel, CFTR included, is simply a gated pore with the capacity to select for particular ions. Biophysical data collected over the past two decades suggest a continuous chloride permeation pathway in CFTR consisting of, from the cytoplasmic side to the extracellular side, a a lateral entrance El Hiani and Linsdell, ; El Hiani et al. In the following subsection, we will use the cryo-EM structure of hCFTR as our major reference to summarize previous functional studies that match these structural features.
A Lateral view of the TMDs featuring a lateral entrance framed by TM4 red and TM6 black , the surface view of the internal vestibule gray , and a nonconductive region where close contacts among TMs obstruct the pore. Other 10 TMs are shown as ribbons in light purple. A yellow dot marks the end of the water-accessible space in the internal vestibule. Of note, the yellow dot is shifted away from the central axis of the pore. The functional implications of this structural feature are discussed in the text. B Top view of the TMDs. Color code is the same as used in A.
Several residues in the external part of the TMDs violet, R; green, D; gold, E; brown, R; salmon, R; yellow, K; and blue, E were reported to affect the stability of the channel architecture or permeation properties.
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The distances between selected residues are shown in dashed lines, and the potential functional significance of these residues is discussed in the text. The first piece of functional evidence for a lateral entrance was provided by El Hiani and Linsdell Interpreting these data in the context of the SAVbased homology model Mornon et al. Furthermore, as introducing a negative charge into positions TM3 , TM4 , TM5 , and TM6 decreases the single-channel current amplitude significantly more than that at positions TM10 and TM10 , it is further suggested that the lateral entrance between TM4 and TM6 serves as a major portal of entry, whereas the entrance between TM10 and TM12 plays a minor role.
The cryo-EM structures indeed confirmed that the side chains of all six positively charged residues protrude into the internal vestibule that is constructed by two pseudo-symmetric flanks of the TMDs. The internal vestibule has two opposing lateral clefts opening toward the cytoplasm: a larger opening framed by TM4 and TM6 consistent with what is proposed El Hiani and Linsdell, , and a smaller one by TM10 and TM This latter opening in the unphosphorylated closed state of hCFTR is unlikely to be conductive because of an obstruction by part of the R domain as elaborated above in the R domain section.
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However, the widest distance between TM4 and TM6 flanking this cleft is But why does the external gate remain closed in this structure with dimerized NBDs? Their data suggest that the TMDs assume an inward-facing conformation in the open state, but an outward-facing conformation in the closed state.
Regardless of these controversies, on a closer look at the conformation of these three cryo-EM structures so far published, the basic architecture of CFTR is consistent with that of ABC exporters Schmitt, ; Dawson and Locher, : when one divides the whole protein into halves by these two potential ion entry ports, one half is constructed by TM1, 2, 3, 6, 10, and 11, and the other by TM7, 8, 9, 12, 4, and 5 Figs.
The color code is the same as in A. However, some modifications of this basic architecture are needed for CFTR to work as a channel an issue discussed throughout this article. The cryo-EM structures also offer an unparalleled opportunity for checking the pore-lining segments proposed based on functional data particularly from SCAM. Table S1 summarizes the published positions of each TM where engineered cysteines can be modified by either internal or external application of thiol modification reagents.
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Through checking the solvent accessibility Lee and Richards, and surface exposure of each residue in the internal vestibule of the cryo-EM hCFTR structure, we found that, with some exceptions elaborated below , many of the pore-lining residues reported in SCAM studies are indeed water accessible in this closed-state cryo-EM structure Table S1. Perhaps the most intriguing and surprising finding in the cryo-EM structures is that the pore is architecturally asymmetrical. The distorted segment of TM8 impinges toward the central vertical axis of the pore. The accompanied lateral displacement of TM7 away from the core of the protein renders TM7 being located at a different position than its counterpart TM1 Fig.
This breakdown of twofold symmetry nicely explains why TM7 does not contribute to the pore formation Wang et al. These structural deviations away from twofold symmetry may explain some of the existing data supporting the asymmetry of the pore.
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For instance, a slight displacement of TM12 medially toward the central axis not only results in an obvious asymmetry in relation to the central axis between TM6 and TM12 but also brings TM12 closer to TM10 to form a smaller lateral entrance between these two segments as discussed above. This different positioning of TM6 and TM12 likely accounts for the functional data that implicate an asymmetrical contribution of these two pivotal TMs in forming the ion permeation pathway Table S1; Gao and Hwang, As elaborated in more detail below, whereas T and S in TM6 may contribute to the formation of the narrowest segment in the pore, there is little functional evidence supporting an equivalent role for residues in TM12 Gao and Hwang, The internal vestibule is shown in a gray surface view.
The dashed box is enlarged in B. B E92 black and K95 dark blue in TM1 form an intra-helical salt bridge. C Top view of the TM pairs in A shows clearly that TM7 is located at the periphery of the protein with little contact with the internal vestibule in gray surface view. Of note, these unexpected asymmetrical structural features can also serve as a guide for further experimental explorations. For example, five yet-to-be-studied residues H, I, H, L, and R in TM2, but none in its counterpart TM8, are solvent accessible in the internal vestibule.
Furthermore, as these atomic structures of CFTR show that the wider internal vestibule becomes narrower as the permeation pathway ascends toward the external end, one expects far more TMs making contributions to pore construction in the cytoplasmic end than at the periplasmic end of the anion permeation pathway. However, so far, the strongest functional data only support TM1 and TM6 as major players in making up the narrow portion of the pore. Thus, it takes at least one more TM to make the way for the last mile of chloride permeation.
The definitive answer to this issue will have to await the solution of an open state, because neither current SCAM data nor available structures are of significant help. Ion channel proteins have evolved to solve a fundamental problem in every living being: the rapid translocation of ions across the insurmountable energetic barrier of lipid bilayers.
For CFTR to work as an effective anion channel, it has to be equipped with the structural characteristics that bestow energetically favorable conditions facilitating every step in the translocation process for an anion. This will include attraction of bulk anions to the cytoplasmic entrance, entry of ions into the pore, sloughing off some of the hydration water molecules to pass through the narrowest region, and final rehydration and exit out of the channel.
Given that the electrostatic charge—charge or charge—dipole interaction is one of the basic laws of the universe, it is reasonable that equivalent design principles should also apply to anion channels. In the absence of an evolutionary pressure for selecting different anions, most anion channels do not need to equip themselves with a highly selective mechanism; they nonetheless do require a mechanism for differentiating anions from cations. Indeed, as discussed above, some positively charged residues, such as K TM3 , R TM4 , and R TM6 , at the cytoplasmic entrance in CFTR may attract chloride from the bulk solution to the channel mouth to ensure a higher chloride conductance through a long-range surface-charge mechanism El Hiani and Linsdell, Some charged residues seen within the internal vestibule such as K95, R, and R Zhang and Chen, ; Liu et al.
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If chloride permeation is indeed facilitated and tuned globally by the charged residues along the permeation pathway following the basic laws of electrostatics, it is not surprising that similar electrostatic forces also work on other negatively charged molecules such as channel blockers. Furthermore, mutations of K95 were also reported to weaken the blocking effects of 4,4-dinitrostilbene-2,2-disulfonic acid, lonidamine, 5-nitro 3-phenylpropylamino benzoate NPPB , or taurolithocholatesulfate Linsdell, Aubin et al.
As the anion translocation—for chloride or large organic anions—is a continuous process and is deemed to be affected by the local electrostatic potential in the internal vestibule, the apparent affinities of anionic blockers are inevitably affected by charge manipulations along their path. Without better evidence, it is inappropriate to assign these charged residues as definitive binding sites for chloride ions or anionic blockers compare Linsdell, ; Rubaiy and Linsdell, Another important role assumed by the positively charged residues in the pore is to neutralize the negatively charged side chains that may pose unfavorable local energetic profile for anion permeation.
For instance, Cui et al. The cryo-EM structures indeed show that R and D, two conserved amino acids, mutations of which are associated with CF, reside on a similar horizontal level in the internal vestibule. Although this charged pair is separated by a distance of In addition, supporting a role of this charge—charge interaction in gating, neutralization of R decreases the P o Cui et al. Although examining the positions of charged residues in the pore, we also noticed an intra-helical salt bridge between E92 and K95 in TM1 Fig.
Because E92 is positioned at a region where the internal vestibule becomes fairly narrow in dimension, it seems critical to neutralize this negative charge to ensure a fast anion movement across the pore. Previous studies indeed showed a drastic decrease of the single-channel amplitude by the K95S or K95Q mutation Zhou et al.
To date, these studies have identified a few externally accessible residues in TM1 Gao et al. Compared with the results from SCAM experiments with internally applied thiol-specific reagents, many fewer positive hits on the external side of the channel suggest that the extracellular vestibule, if it exists, is much shallower than the internal vestibule.
In contrast, much larger effects were observed only for a few positions in TM1 e. Without further experimental evidence, we should be cautious in assigning the role of TM5, 9, 11, and 12 in the construction of the external portion of the pore.
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