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PR01116

Identifier
CLCHANNEL5  [View Relations]  [View Alignment]  
Accession
PR01116
No. of Motifs
3
Creation Date
26-APR-1999
Title
CLC-5 chloride channel signature
Database References
PRINTS; PR00762 CLCHANNEL
INTERPRO; IPR002247
Literature References
1. JENTSCH, T.J. AND GUNTHER, W.
Chloride channels: an emerging molecular picture.
BIOESSAYS 19 117-126 (1997).
 
2. JENTSCH, T.J., STEINMEYER, K. AND SCHWARZ, G.
Primary structure of Torpedo marmorata chloride channel isolated by
expression cloning in Xenopus oocytes.
NATURE 348 510-514 (1990).
 
3. SCHMIDT-ROSE, T. AND JENTSCH, T.J.
Transmembrane topology of a CLC chloride channel.
PROC.NATL.ACAD.SCI.U.S.A. 94 7633-7638 (1997).
 
4. LEHMANN-HORN, F., MAILANDER, V., HEINE, R. AND GEORGE, A.L.
Myotonia levior is a chloride channel disorder.
HUM.MOL.GENET. 4 1397-1402 (1995).
 
5. LLOYD, S.E., PEARCE, S.H.S., FISHER, S.E., STEINMEYER, K.,
SCHWAPPACH, B., SCHEINMAN, S.J., HARDING, B., BOLINO, A., DEVOTO, M.,
GOODYER, P., RIGDEN, S.P.A., WRONG, O., JENTSCH, T.J., CRAIG, I.W. AND
THAKKER, R.V.
A common molecular basis for three inherited kidney stone diseases.
NATURE 379 445-449 (1996).
 
6. STEINMEYER, K., SCHWAPPACH, B., BENS, M., VANDEWALLE, A. AND
JENTSCH, T.J.
Cloning and functional expression of rat CLC-5, a chloride channel related
to kidney disease.
J.BIOL.CHEM. 270 31172-31177 (1995).
 
7. FRIEDRICH, T., BREIDERHOFF, T. AND JENTSCH, T.J.
Mutational analysis demonstrates that ClC-4 and ClC-5 directly mediate
plasma membrane currents.
J.BIOL.CHEM. 274 896-902 (1999).
 
8. GUNTHER, W., LUCHOW, A., CLUZEAUD, F., VANDEWALLE, A. AND JENTSCH, T.J.
ClC-5, the chloride channel mutated in Dent's disease, colocalizes with
the proton pump in endocytotically active kidney cells.
PROC.NATL.ACAD.SCI.U.S.A. 95 8075-8080 (1998).

Documentation
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 [1].
 
The first member of the family (CLC-0) was expression-cloned from the
electric organ of Torpedo marmorata [2], and subsequently nine CLC-like
proteins have been cloned from mammals. They are thought to function as
multimers of two or more identical or homologous 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 [2]. 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 cytoplasm [3].
 
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 [4]. Similarly, mutations
in CLCN5, which encodes CLC-5, a renal Cl- channel, lead to several forms 
of inherited kidney stone disease [5]. These mutations have been
demonstrated to reduce or abolish CLC function.
 
CLC-5, with 746 amino acid residues, is a member of the CLC family that
shows most similarity to the CLC-3 and CLC-4 channels, to which it is ~80%
identical at the amino acid level. It is predominantly expressed in the
kidney, but can be found in the brain and liver [6]. As mentioned above,
mutations in the CLCN5 gene cause certain hereditary kidney stone diseases,
including Dent's disease, an X-chromosome linked syndrome characterised by 
proteinuria, hypercalciuria, and kidney stones (nephrolithiasis), leading to
progressive renal failure. When the native protein is expressed, it gives
rises to strongly outwardly-rectifying Cl- currents; however, the mutated
channel forms show loss-of-function [6,7]. Recent studies have suggested 
that CLC-5 may play an important role in endocytosis in renal proximal
tubule cells (probably by providing a shunt for the potential generated by
the H+-ATPase), and that disruption of this function may impair endocytosis,
accounting for the proteinuria observed in Dent's disease (8).
 
CLCHANNEL5 is a 3-element fingerprint that provides a signature for the
CLC-5 voltage-gated Cl- channel. The fingerprint was derived from an initial
alignment of 2 sequences: the motifs were drawn from conserved regions 
spanning virtually the full alignment length, focusing on those sections
that characterise the CLC-5 isoform but distinguish it from others - motif 1
resides within the putative cytoplasmic N-terminus; motif 2 encodes the
C-terminal half of the fourth hydrophobic domain; and motif 3 resides within
the putative cytoplasmic C-terminus. Two iterations on SPTR37_9f were
required to reach convergence, at which point a true set comprising 3
sequences was identified.
Summary Information
3 codes involving  3 elements
0 codes involving 2 elements
Composite Feature Index
3333
2000
123
True Positives
CLC5_HUMAN    CLC5_RAT      O13080        
Sequence Titles
CLC5_HUMAN  CHLORIDE CHANNEL PROTEIN 5 (CLC-5) - HOMO SAPIENS (HUMAN). 
CLC5_RAT CHLORIDE CHANNEL PROTEIN 5 (CLC-5) - RATTUS NORVEGICUS (RAT).
O13080 CHLORIDE CHANNEL CLC-5 - XENOPUS LAEVIS (AFRICAN CLAWED FROG).
Scan History
SPTR37_9f  2  250  NSINGLE    
Initial Motifs
Motif 1  width=10
Element Seqn Id St Int Rpt
TWALIHSVSD CLC5_HUMAN 44 44 -
TWALIHSVSD CLC5_RAT 44 44 -

Motif 2 width=9
Element Seqn Id St Int Rpt
NILCHCFNK CLC5_HUMAN 223 169 -
NILCHCFNK CLC5_RAT 223 169 -

Motif 3 width=8
Element Seqn Id St Int Rpt
VVSTSIIY CLC5_HUMAN 654 422 -
VVSTSIIY CLC5_RAT 654 422 -
Final Motifs
Motif 1  width=10
Element Seqn Id St Int Rpt
TWALIHSVSD CLC5_HUMAN 44 44 -
TWALIHSVSD CLC5_RAT 44 44 -
TWALLHSVSD O13080 106 106 -

Motif 2 width=9
Element Seqn Id St Int Rpt
NILCHCFNK CLC5_HUMAN 223 169 -
NILCHCFNK CLC5_RAT 223 169 -
NILCHLFTK O13080 285 169 -

Motif 3 width=8
Element Seqn Id St Int Rpt
VVSTSIIY CLC5_HUMAN 654 422 -
VVSTSIIY CLC5_RAT 654 422 -
IVSTSRIY O13080 716 422 -