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PR01115

Identifier
CLCHANNEL4  [View Relations]  [View Alignment]  
Accession
PR01115
No. of Motifs
5
Creation Date
26-APR-1999
Title
CLC-4 chloride channel signature
Database References
PRINTS; PR00762 CLCHANNEL
INTERPRO; IPR002246
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. VAN SLEGTENHORST, M.A., BASSI, M.T., BORSANI, G., WAPENAAR, M.C.,
FERRERO, G.B., DE CONCILIIS, L., RUGARLI, E.I., GRILLO, A., FRANCO, B.,
ZOGHBI, H.Y. AND BALLABIO, A.
A gene from the Xp22.3 region shares homology with voltage-gated chloride
channels.
HUM.MOL.GENET. 3 547-552 (1994).
 
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).

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-4 was initially identified as a putative member of the CLC family 
following mapping of the human Xp22.3 chromosome region [6]. Together with
CLC-5 and CLC-3, it forms a distinct branch of the CLC gene family. Initial
expression studies of CLC-4 did not yield measurable Cl- currents; however,
recent studies of human CLC-4 have revealed that it gives rise to Cl- 
currents that rapidly activate at positive voltages, and are sensitive to
extracellular pH, with currents decreasing when pH falls below 6.5 [7].
 
CLCHANNEL4 is a 5-element fingerprint that provides a signature for the
CLC-4 voltage-gated Cl- channel. The fingerprint was derived from an initial
alignment of 3 sequences: the motifs were drawn from conserved regions
within the C-terminal two thirds of the alignment, focusing on those
sections that characterise the CLC-4 isoform but distinguish it from others
- motif 1 resides within the fourth hydrophilic domain; motifs 2 and 3 lie 
within the seventh and ninth hydrophilic domains, respectively; and motifs
4-5 reside within the putative cytoplasmic C-terminus. A single iteration 
on SPTR37_9f was required to reach convergence, no further sequences being
identified beyond the starting set. 
Summary Information
3 codes involving  5 elements
0 codes involving 4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
533333
400000
300000
200000
12345
True Positives
CLC4_HUMAN    CLC4_MOUSE    CLC4_RAT      
Sequence Titles
CLC4_HUMAN  CHLORIDE CHANNEL PROTEIN 4 (CLC-4) - HOMO SAPIENS (HUMAN). 
CLC4_MOUSE CHLORIDE CHANNEL PROTEIN 4 (CLC-4) - MUS MUSCULUS (MOUSE).
CLC4_RAT CHLORIDE CHANNEL PROTEIN 4 (CLC-4) - RATTUS NORVEGICUS (RAT).
Scan History
SPTR37_9f  1  200  NSINGLE    
Initial Motifs
Motif 1  width=8
Element Seqn Id St Int Rpt
FFSSLFSK CLC4_HUMAN 237 237 -
FFSSLFSK CLC4_RAT 224 224 -
FFSSLFSK CLC4_MOUSE 224 224 -

Motif 2 width=10
Element Seqn Id St Int Rpt
INDPNMTRPV CLC4_HUMAN 417 172 -
INDPNMTRPV CLC4_RAT 404 172 -
INDPNMTRPV CLC4_MOUSE 404 172 -

Motif 3 width=8
Element Seqn Id St Int Rpt
FRNWCRPG CLC4_HUMAN 500 73 -
FRNWCRPG CLC4_RAT 487 73 -
FRNWCRPG CLC4_MOUSE 487 73 -

Motif 4 width=9
Element Seqn Id St Int Rpt
TLIKETDYN CLC4_HUMAN 624 116 -
TLIKETDYN CLC4_RAT 611 116 -
TLIKETDYN CLC4_MOUSE 611 116 -

Motif 5 width=7
Element Seqn Id St Int Rpt
QRRELIL CLC4_HUMAN 650 17 -
QRRELIL CLC4_RAT 637 17 -
QRRELIL CLC4_MOUSE 637 17 -
Final Motifs
Motif 1  width=8
Element Seqn Id St Int Rpt
FFSSLFSK CLC4_HUMAN 237 237 -
FFSSLFSK CLC4_RAT 224 224 -
FFSSLFSK CLC4_MOUSE 224 224 -

Motif 2 width=10
Element Seqn Id St Int Rpt
INDPNMTRPV CLC4_HUMAN 417 172 -
INDPNMTRPV CLC4_RAT 404 172 -
INDPNMTRPV CLC4_MOUSE 404 172 -

Motif 3 width=8
Element Seqn Id St Int Rpt
FRNWCRPG CLC4_HUMAN 500 73 -
FRNWCRPG CLC4_RAT 487 73 -
FRNWCRPG CLC4_MOUSE 487 73 -

Motif 4 width=9
Element Seqn Id St Int Rpt
TLIKETDYN CLC4_HUMAN 624 116 -
TLIKETDYN CLC4_RAT 611 116 -
TLIKETDYN CLC4_MOUSE 611 116 -

Motif 5 width=7
Element Seqn Id St Int Rpt
QRRELIL CLC4_HUMAN 650 17 -
QRRELIL CLC4_RAT 637 17 -
QRRELIL CLC4_MOUSE 637 17 -