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Transmembrane topology of a CLC chloride channel.
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Chloride channels (CLCs) constitute an evolutionarily well-conserved family
of voltage-gated channels that are structurally unrelated to the other
known voltage-gated channels. They are found in organisms ranging from
bacteria to yeasts and plants, and also to animals. Their functions in
higher animals likely include the regulation of cell volume, control of
electrical excitability and trans-epithelial transport .
The first member of the family (CLC-0) was expression-cloned from the
electric organ of Torpedo marmorata , and subsequently nine CLC-like
proteins have been cloned from mammals. They are thought to function as
multimers of two or more identical or similar subunits, and they have
varying tissue distributions and functional properties. To date, CLC-0,
CLC-1, CLC-2, CLC-4 and CLC-5 have been demonstrated to form functional
Cl-channels; whether the remaining isoforms do so is either contested or
unproven. One possible explanation for the difficulty in expressing
activatable Cl- channels is that some of the isoforms may function as Cl-
channels of intracellular compartments, rather than of the plasma membrane.
However, they are all thought to have a similar transmembrane (TM)
topology, initial hydropathy analysis suggesting 13 hydrophobic stretches
long enough to form putative TM domains . Recently, the postulated TM
topology has been revised, and it now seems likely that the CLCs have 10
(or possibly 12) TM domains, with both N- and C-termini residing in the
A number of human disease-causing mutations have been identified in the
genes encoding CLCs. Mutations in CLCN1, the gene encoding CLC-1, the major
skeletal muscle Cl- channel, lead to both recessively and dominantly-
inherited forms of muscle stiffness or myotonia . Similarly, mutations
in CLCN5, which encodes CLC-5, a renal Cl- channel, lead to several forms
of inherited kidney stone disease . These mutations have been
demonstrated to reduce or abolish CLC function.
CLCHANNEL is a 7-element fingerprint that provides a signature for the major
skeletal muscle chloride channel proteins. The fingerprint was derived from
an initial alignment of 15 sequences: the motifs were drawn from conserved
regions spanning the N-terminal half of the alignment: motif 1 lies between
putative TM regions 2 and 3; motifs 2-5 lie in the third, fifth, tenth and
eleventh TM regions; motif 6 includes part of the twelfth TM region; and
motif 7 lies in the cytoplasmic domain preceding the final TM region. Three
iterations on OWL29.4 were required to reach convergence, at which point a
true set comprising 46 sequences was identified. Several partial matches
were also found, all of which are fragments and family members that fail to
make significant matches with one or more motifs.
An update on SPTR37_9f identified a true set of 50 sequences, and 14