THE JOURNAL OF BIOLOGICAL CHEMISTRY
Minireview
Cystic Fibrosis Transmembrane
Conductance Regulator
STRUCTURE AND FUNCTION OF AN EPITHELIAL
CHLORIDE CHANNEL*
Myles H. Akabas
From the Center for Molecular Recognition,
Departments of Physiology & Cellular Biophysics
and Medicine, Columbia University,
New York, New York 10032
The cystic fibrosis transmembrane conductance regulator
(CFTR)1 forms a Cl channel that is an essential component of
epithelial Cl transport systems in many organs, including the
intestines, pancreas, lungs, sweat glands, and kidneys. In the
Cl secretory intestinal epithelium, Cl enters the cells
through a Na-K-2Cl cotransporter in the basolateral mem-
brane and exits through CFTR in the apical membrane; water
follows osmotically (1). Absorptive epithelia use similar trans-
porters and channels, but their polarized distribution between
the apical and basolateral membranes is usually reversed. A
major determinant of the transepithelial Cl transport rate is
the level of activation of CFTR (2, 3), which depends on the
extent to which it is phosphorylated. This is determined by the
relative activities of kinases and phosphatases, the activities of
which are often hormonally regulated (1).
Defects in the gene encoding CFTR that reduce either its Cl
transport capacity or its level of cell surface expression cause
cystic fibrosis (CF) (4 6) as well as a form of male sterility due
to congenital bilateral absence of the vas deferens (7). CF is the
most common lethal genetic disease in Caucasians, with about
30,000 CF patients in the United States. In contrast, in intes-
tinal epithelial cells overstimulation of CFTR because of the
activation of protein kinases by bacterial enterotoxins causes
secretory diarrhea (1, 8). Secretory diarrhea is the second larg-
est cause of infant mortality in the developing world, causing 3
million deaths per year of children under the age of 5. Thus,
although CFTR was named because of its association with CF,
as a cause of disease, its relationship to secretory diarrhea is a
more widespread public health problem.
The cloning of CFTR in 1989 (9) has facilitated studies of its
structure, function, regulation, biogenesis, and degradation,
which will be reviewed in this article. Issues reviewed else-
where and not discussed here include the mechanisms by
which mutations in CFTR cause CF (5, 6) and the possible role
* This minireview will be reprinted in the 2000 Minireview Compen-
dium, which will be available in December, 2000. This work was sup-
ported in part by National Institutes of Health Grant DK51794 and an
Established Scientist Award from the New York City Affiliate of the
American Heart Association.
To whom correspondence should be addressed: Center for Molecular
Recognition, Depts. of Physiology & Cellular Biophysics and Medicine,
Columbia University, 630 W. 168th St., New York, NY 10032. Tel.:
212-305-3974; Fax: 212-305-5594; E-mail: ma14@columbia.edu.
1
The abbreviations used are: CFTR, cystic fibrosis transmembrane
conductance regulator; CF, cystic fibrosis; DIDS, 4,4-diisothiocyanos-
tilbene-2,2-disulfonic acid; MDR, multiple drug resistance protein;
NBD, nucleotide-binding domain; PKA, cAMP-dependent protein ki-
nase; PKC, protein kinase C; ER, endoplasmic reticulum.
This paper is available on line at http://www.jbc.org
Vol. 275, No. 6, Issue of February 11, pp. 3729 3732, 2000
2000 by The American Society for Biochemistry and Molecular Biology, Inc.
Printed in U.S.A.
of CFTR in regulating the pH within intracellular organelles
(10).
Structural Basis of Channel Function
CFTR is a member of the ATP-binding cassette (ABC) mem-
brane transporter gene superfamily that includes both eukary-
otic and bacterial proteins, such as the multiple drug resistance
protein (MDR), the sulfonylurea receptor, the transporter for
antigen presentation, and the bacterial periplasmic permeases
(9, 11). Being an ion channel makes CFTR unique in this gene
superfamily in which most other members are ATP-driven
membrane transporters.
CFTR contains 1480 amino acids and consists of two homol-
ogous halves (Fig. 1). Each half contains six membrane-span-
ning segments and a nucleotide-binding domain (NBD). The
two halves of CFTR are linked by a cytoplasmic regulatory
domain (R-domain) that contains a number of consensus phos-
phorylation sites (9). In the proposed transmembrane topology
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(Fig. 1), which is supported by experimental evidence (9, 12,
13), 77% of the protein is in the cytoplasm, 19% in membrane-
spanning segments, and 4% in extracellular loops, which (ex-
cept for the M1M2 and M7M8 loops) are very short. The
M7M8 loop contains two N-linked glycosylation sites that are
used in vivo (12, 13). Covalent linkage of the two halves is not
required for assembly and function. When expressed as sepa-
rate proteins in the same cells the halves assembled into func-
tional channels and could be co-immunoprecipitated. This as-
sembly required interactions within the membrane-spanning
domains (13, 14).
CFTR was inferred to be a monomer because following solu-
bilization, with either ionic or nonionic detergents, biochemi-
cally distinct forms of CFTR, expressed in the same cells, could
not be co-immunoprecipitated (15). In contrast, two studies
concluded that CFTR is a homodimer in situ based on the size
of CFTR particles in freeze-fracture electron micrographs (16)
and on the functional effects of coexpressing mutants with
distinct functional properties (17). In the homologous MDR
transporter, however, dimers were not seen in cryoelectron
microscopic images (18).
Channel-lining ResiduesThe channel lining is formed, at
least in part, by residues from among the 12 membrane-span-
ning segments. The major determinants of the channels func-
tional properties are likely to be among the channel-lining
residues. Water-accessible residues inferred to line the channel
were identified in the M1, M3, and M6 segments using the
substituted cysteine accessibility method (19 21). These seg-
ments secondary structure was inferred to be largely -helical
based on the patterns formed by the channel-lining residues
(19 21). Further support for an -helical secondary structure
of the membrane-spanning segments was provided by studies
of synthetic peptides, the sequences of which corresponded to
those of the M1M6 segments. These peptides were largely
-helical in liposomes and in detergent micelles (22, 23).
The minimum channel diameter was inferred to be 5.3
based on the size of the largest permeant anion (24). Further
studies using patches with larger numbers of channels showed
that anions as large as lactobionate (10 13 in diameter) were
slightly permeable. Thus, at least transiently, the diameter of
the channel must be 10 13 (25). In the presence of cytoplas-
mic ATP the large anions were only permeable from the cyto-
plasmic side (25). The molecular basis for asymmetric perme-
3729
3730 Minireview: CFTR Channel Structure and Function
FIG. 1. Transmembrane topology of CFTR. Gray balloons on the
M7M8 loop indicate N-linked glycosylation sites. R, R-domain.
ation by large anions is unknown. There is no asymmetry in the
conduction of small anions; the channel has a linear current-
voltage relationship in Cl solutions (13). Although some stud-
ies suggested that ATP was permeable through CFTR (re-
viewed in Ref. 26), it has been convincingly demonstrated that
there is no measurable electrogenic ATP flux through CFTR
(2729).
Mechanism of Charge SelectivityThe ability to discrimi-
nate between Cl and cations is essential for the role of CFTR
in epithelial Cl transport. The extent of anion selectivity, as
measured by the Cl to Na permeability ratio (30), ranges
between 10 and 300 (31, 32). We showed that the charge selec-
tivity filter that discriminates between anions and cations is
located at the cytoplasmic end of the channel and that both
anions and cations can enter the extracellular end of the chan-
nel (33). Arg-352, at the cytoplasmic end of M6, is a major
determinant of charge selectivity. Removal of the positive
charge at this position reduced the Cl to Na permeability
ratio approximately 10-fold (34). We hypothesized that the
positive charge of Arg-352 creates an electrostatic barrier to
cation permeation. Near Arg-352 the channel must be narrow
enough so that the electrostatic barrier extends across the
channel lumen (34).
Halide Selectivity and Multiple Ion OccupancyThe channel
displays modest selectivity between halides. The halide perme-
ability sequence is I (1.8) Br (1.2) Cl (1.0) F (0.2), mic end where the charge selectivity filter is located. Finally,
indicative of weak interactions between permeating anions and
channel binding sites (30, 32). Multiple anions can simulta-
neously occupy the channel, thereby resulting in anomalous
mole fraction effects in the single channel conductance in mix-
tures of Cl and SCN. These effects were eliminated in the
M6 mutant R347D, and Arg-347, therefore, was hypothesized
to be at or near an anion binding site (35). Arg-347, however,
has been shown to form a salt bridge with Asp-924 (36). There-
fore, it is possible that rather than Arg-347 being a binding site
itself, structural perturbation caused by the loss of the salt
bridge disrupted an anion binding site elsewhere (30).
Channel InhibitorsCFTR has few inhibitors and none are
of high affinity or specificity (13). The affinity of the channel
blocker diphenylamine 2-carboxylate was reduced by mutating
two water-accessible residues in M6. Mutations of the aligned
M12 residues increased diphenylamine 2-carboxylate affinity
suggesting that the channel is lined by residues from both
halves of CFTR (37).
In contrast to their actions on other Cl channels and trans-
porters, disulfonic stilbenes such as DIDS inhibit only when
applied to the cytoplasmic side (38). Cytoplasmic application of
other large anions also caused flickery block of CFTR. This is
further evidence that the channel is asymmetric and contains
an anion binding site in the cytoplasmic vestibule (39). The
residues forming the cytoplasmic vestibule remain to be iden-
tified, but the cytoplasmic loops probably do not contribute to
FIG. 2. Schematic illustrating the structure of CFTR and the
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relationships of its domains and associated proteins to the
channel. Membrane-spanning domains, red; the water-filled trans-
membrane channel, blue; NBD-1, yellow; NBD-2, orange; bound ATP,
white ovals; R-domain, green; the N- and C termini are indicated by
black lines; the associated proteins syntaxin 1A (Syn 1A) and Na/H
exchanger regulatory factor/ezrin-binding protein 50 (NHERF/EBP-
50), purple. Note the position of Arg-352, a major determinant of charge
selectivity, at the narrow point in the channel. Cl ions probably do not
interact with the NBDs and R-domain as they pass through the chan-
nel. The cytoplasmic vestibule has a binding site for large anions (see
channel-lining Residues). The interactions with PP2C and other chan-
nels and transporters are not shown (see Interactions with Other
Proteins).
the vestibule because none of the CF-related loop mutations
affected ion conduction (40).
The picture that is emerging is of a channel with a large
extracellular vestibule that extends into the plain of the mem-
brane and is accessible to anions and cations from the extra-
cellular side (Fig. 2). The channel narrows toward the cytoplas-
there is a short cytoplasmic vestibule that contains an anion
binding site. The channel lining is formed, in part, by residues
from the M1, M3, M6, and M12 segments. Little is known about
whether the other eight membrane-spanning segments contrib-
ute to the channel lining. The location of the gate that blocks
ion conduction through the channel in the closed state is un-
known. The gate, however, is controlled by conformational
changes in the cytoplasmic domains.
Regulation of CFTR Channel Gating
Two separate processes control the gating of CFTR: 1) phos-
phorylation and 2) binding and hydrolysis of ATP. Phosphoryl-
ation is necessary for activation, but it is not sufficient. After
phosphorylation, gating between the closed and open states is
controlled by ATP hydrolysis (12, 13, 41).
Phosphorylation Is a Prerequisite for Channel Activation
The R-domain contains multiple consensus phosphorylation
sites for cAMP-dependent protein kinase (PKA), protein kinase
C (PKC), and Type II cGMP-dependent protein kinase (9, 12,
13, 41, 42). The more extensive the phosphorylation, the
greater the channel open probability (41, 43). There appears to
be extensive redundancy in the regulatory PKA phosphoryla-
tion sites. Five sites are phosphorylated in vivo, but removal of
these sites or all 10 dibasic PKA sites reduced but did not
eliminate PKA activation (44). CFTR is still phosphorylated
after removal of the 10 dibasic sites indicating that phospho-
 Minireview: CFTR Channel Structure and Function
rylation at non-dibasic PKA sites is sufficient for channel acti-
vation; one such site has been identified (12, 13, 41). PKC
phosphorylation may be a prerequisite for activation by PKA
(45). Finally, although genistein, a tyrosine kinase inhibitor,
activates CFTR this occurs through a direct interaction with
CFTR and does not involve a tyrosine kinase (reviewed in Ref.
41).
After phosphorylation, CFTR is deactivated by protein phos-
phatases (41). Dephosphorylation is largely mediated by pro-
tein phosphatases PP2C and PP2A (46, 47). PP2C is closely
linked to CFTR in the membrane as it could be co-immunopre-
cipitated with CFTR as well as cross-linked to CFTR by bifunc-
tional cross-linkers, whereas PP1, PP2A, and PP2B could not
(48).
Channel Gating Requires ATP HydrolysisFollowing phos-
phorylation, opening and closing of the channel is controlled by
ATP binding and hydrolysis (12, 13, 41). Non-hydrolyzable ATP
analogs do not support channel opening (49). Purified, phos-
phorylated, reconstituted CFTR binds ATP with a Km of 0.3 mM
and hydrolyzes ATP at a rate of about 1 molecule/s (50), similar
to the rate of channel gating. ATP hydrolysis occurs in the
NBDs, which contain highly conserved Walker A and B motifs
found in other ATPases (9, 13, 41, 49).
A construct lacking the R-domain, CFTR-R, did not require
phosphorylation to open and close in the presence of ATP (13).
Adding soluble, phosphorylated R-domain peptide to CFTR-R
enhanced its ATP sensitivity resulting in an increased channel
open probability (51, 52). Thus, the R-domain interacts with
the NBDs and regulates their ATP affinity.
Structure of a Bacterial NBDIn the homologous bacterial
periplasmic permeases the NBDs and the transmembrane do-
mains are usually separate gene products that assemble during
biosynthesis (11, 53). The histidine periplasmic permease con-
tains two copies of its NBD protein, HisP; each copy has a
single nucleotide binding site. The x-ray crystal structure of
HisP was determined (54). The sequence conservation between
the bacterial and eukaryotic NBDs implies that their struc-
tures are similar and that aligned residues perform similar
functions in HisP and CFTR.
HisP has a novel structure (54). It contains only small re-
gions of structural similarity with RecA and the and F1-
ATPase subunits. HisP is shaped like the letter L (Fig. 2). One
arm (Arm I) of the L contains the ATP binding site, including
the Walker A and B motifs. Most interactions between the
Walker A residues and ATP are via hydrogen bonds between
the backbone amides and the ATP phosphates. An aspartate at
the C terminus of the Walker B motif, aligned with CFTR
residues Asp-572 and Asp-1370, in NBD-1 and -2, respectively,
was inferred to bind the Mg2 ion required for hydrolysis.
CFTR residues Gln-493 and Ser-573 in NBD-1 and Gln-1291
and Glu-1371 in NBD-2 align with the catalytically important
residues in HisP that hydrogen bond to a water molecule that
in turn hydrogen bonds to the -phosphate. This water mole-
cule is thought to attack ATP because its hydrogen bond lies
parallel to the P-O bond that is broken during ATP hydrol-
ysis (54). The adenine base forms a hydrophobic interaction
with a single aromatic residue, perhaps explaining the lack of
specificity among nucleotide triphosphates that can gate CFTR
(49).
The other arm in the HisP structure, Arm II, contains a
LSGGQ motif that forms the foundation around which Arm II
is built. Arm II was inferred to interact with the membrane-
spanning domains (54). The residue aligned with Phe-508 in
CFTR, the site of the most common CF-associated mutation,
lies on an exposed surface of an -helix in Arm II.
Channel Gating and the Sites of ATP HydrolysisThe cur-
3731
rent hypothesis that ATP hydrolysis at NBD-1 opens the chan-
nel and ATP hydrolysis at NBD-2 closes the channel to termi-
nate a burst is consistent with the functional effects of
mutations in the NBDs (13, 41). Mutations in the NBD-2
Walker motifs that decrease its ATP hydrolysis rate slow chan-
nel closing (5558). Similar mutations in NBD-1 reduce chan-
nel opening. The NBD-1 mutations also altered channel closing
rates, suggesting there are functional interactions between the
NBDs (5557). In both the crystal structure and in solution
HisP forms a dimer, the interface of which is located along the
edge of Arm I (54). Thus, direct contacts between the NBDs
may be the structural basis for the functional interaction. Mix-
tures of ATP and non-hydrolyzable analogs lock channels in the
open state. Presumably ATP hydrolysis at NBD-1 opens the
channels and binding of a non-hydrolyzable analog at NBD-2
prevents closing (13, 41).
The gating behavior of CFTR has been described by several
kinetic models. Cyclic models with essentially irreversible
steps corresponding to the ATP hydrolysis steps provide the
best descriptions of channel gating (reviewed in Refs. 13, 41,
and 59).
Interactions with Other Proteins
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In addition to its function as a Cl channel, CFTR acts as a
regulator of other channels and transporters (26). CFTR medi-
ates cAMP regulation of amiloride-sensitive Na channels (60),
outward rectifying Cl channels (61, 62), Cl/HCO3 exchanger
(63), and the ROMK K channel (26). Whether these regulatory
functions result from direct interactions between CFTR and
the channels and transporters or through indirect interactions
via other proteins remains to be determined.
Direct interactions with CFTR have been shown for several
proteins. Syntaxin 1A interacts with the cytoplasmic N-termi-
nal domain of CFTR and inhibits channel activity (64). A family
of PDZ-binding domain proteins, including the Na/H ex-
changer regulatory factor (65) and ezrin-binding protein 50
(66), bind to the C terminus (D-(S/T)-X-L) (Fig. 2). These pro-
teins presumably couple CFTR to the cytoskeleton and may be
involved in apical membrane localization. Finally, as men-
tioned above, CFTR is closely associated with protein phospha-
tase 2C (48).
Synthesis and Degradation
Attention has focused on the synthesis and degradation of
CFTR because many mutations that cause CF, such as F508,
lead to the misfolding of CFTR in the endoplasmic reticulum
(ER) and subsequent degradation of CFTR (reviewed in Refs. 4
and 67). The synthesis of wild-type CFTR is inefficient. Only
about 30% of newly synthesized CFTR develops endoglycosi-
dase H-resistant mature glycosylation suggestive of transloca-
tion from the ER to the Golgi complex (68, 69). In contrast,
100% of the homologous MDR matures (70). CFTR molecules
that fail to mature are polyubiquitinated and degraded via a
cytoplasmic, proteasome-dependent pathway (71, 72). In the
ER, CFTR transiently associates with several chaperones in-
cluding the cytoplasmic Hsp70 and Hsp90 and the ER mem-
brane chaperone calnexin (67, 73). The molecular basis for the
inefficient processing of CFTR in the protein synthetic pathway
remains to be elucidated.
Conclusions
CFTR has an important role in epithelial Cl transport both
as a Cl channel and as a regulator of other channels and
transporters. Studies of the channel have begun to provide a
picture of its structure and regulation. Understanding how
CFTR interacts with other channels and transporter will pro-
vide insights into the cellular regulation of epithelial transport
and the pathophysiology that results from defects in CFTR or
3732 Minireview: CFTR Channel Structure and Function
from its overstimulation by bacterial toxins. One hopes that
further studies will provide a basis for the design or identifi-
cation of specific, high affinity CFTR inhibitors that would be
useful for basic studies of the role of CFTR in epithelial Cl
transport and potentially as a therapy for secretory diarrhea, a
major cause of morbidity and infant mortality in the developing
world.
AcknowledgmentI thank Dr. Jonathan Javitch for comments on
this manuscript.
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 Cystic Fibrosis Transmembrane Conductance Regulator: STRUCTURE AND
FUNCTION OF AN EPITHELIAL CHLORIDE CHANNEL
Myles H. Akabas
J. Biol. Chem. 2000, 275:3729-3732.
doi: 10.1074/jbc.275.6.3729

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