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PR01117

Identifier
CLCHANNEL6  [View Relations]  [View Alignment]  
Accession
PR01117
No. of Motifs
5
Creation Date
26-APR-1999
Title
CLC-6 chloride channel signature
Database References
PRINTS; PR00762 CLCHANNEL
PRODOM; PD013312; PD013313; PD037884
INTERPRO; IPR002248
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. BRANDT, S. AND JENTSCH, T.J.
CLC-6 and CLC-7 are two broadly expressed members of the CLC chloride
channel family.
FEBS LETT. 377 15-20 (1995).
 
7. EGGERMONT, J., BUYSE, G., VOETS, T., TYTGAT, J., DE SMEDT, H.,
DROOGMANS, G. AND NILIUS, B.
Alternative splicing of ClC-6 (a member of the ClC chloride-channel
family) transcripts generates three truncated isoforms one of which,
ClC-6c, is kidney-specific.
BIOCHEM.J. 325 269-276 (1997).

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-6 is a CLC that, together with CLC-7, forms a distinct branch of the
CLC gene family. CLC-6 consists of 869 amino acids residues (human isoform)
and is ~45% identical to CLC-7 (at the amino acid level). CLC-6 is broadly
expressed, but, to date, functional studies have not generated measurable
Cl- currents; its identification as a functional Cl- channel therefore
remains putative [6]. Analysis of human CLC-6 mRNAs reveals that transcripts
of the encoding gene (CLCN6) are alternatively-spliced, resulting in the
expression of four different CLC-6 isoforms (CLC-6a to CLC-6d). These show 
different levels of abundance and tissue distribution patterns, with one,
CLC-6c, apparently being a kidney-specific isoform [7].
 
CLCHANNEL6 is a 5-element fingerprint that provides a signature for the
CLC-6 voltage-gated Cl- channel. The fingerprint was derived from an initial
alignment of 2 sequences: the motifs were drawn from conserved regions
within the N-terminal quarter of the alignment, focusing on those regions
that characterise the CLC-6 isoform but distinguish it from others - motif
1 resides within the putative cytoplasmic N-terminus; motif 2 spans the
extremity of the N-terminus, and the following first hydrophobic domain;
motif 3 encodes the C-terminal of the first hydrophobic domain, and the
first 9 residues of the second hydrophilic domain; and motifs 4-5 lie
within the fourth hydrophobic domain. Two iterations on SPTR37_9f were
required to reach convergence, at which point a true set comprising 5
sequences was identified.
Summary Information
5 codes involving  5 elements
0 codes involving 4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
555555
400000
300000
200000
12345
True Positives
CLC6_HUMAN    CLC6_MOUSE    Q99427        Q99428        
Q99429
Sequence Titles
CLC6_HUMAN  CHLORIDE CHANNEL PROTEIN 6 (CLC-6) (KIAA0046) - HOMO SAPIENS (HUMAN). 
CLC6_MOUSE CHLORIDE CHANNEL PROTEIN 6 (CLC-6) - MUS MUSCULUS (MOUSE).
Q99427 CLC-6 CHLORIDE CHANNEL - HOMO SAPIENS (HUMAN).
Q99428 CHLORIDE CHANNEL - HOMO SAPIENS (HUMAN).
Q99429 CHLORIDE CHANNEL - HOMO SAPIENS (HUMAN).
Scan History
SPTR37_9f  2  300  NSINGLE    
Initial Motifs
Motif 1  width=13
Element Seqn Id St Int Rpt
AGCRGSLCCCCRW CLC6_HUMAN 2 2 -
AGCRGSVCCCCRW CLC6_MOUSE 2 2 -

Motif 2 width=10
Element Seqn Id St Int Rpt
AVKWMVVFAI CLC6_HUMAN 78 63 -
AVKWMVVFAI CLC6_MOUSE 78 63 -

Motif 3 width=13
Element Seqn Id St Int Rpt
VDFFVRLFTQLKF CLC6_HUMAN 98 10 -
VDFSVRLFTQLKF CLC6_MOUSE 98 10 -

Motif 4 width=10
Element Seqn Id St Int Rpt
MIHSGSVVGA CLC6_HUMAN 203 92 -
MIHSGAVVGA CLC6_MOUSE 203 92 -

Motif 5 width=10
Element Seqn Id St Int Rpt
LPQFQSISLR CLC6_HUMAN 214 1 -
LPQFQSISLR CLC6_MOUSE 214 1 -
Final Motifs
Motif 1  width=13
Element Seqn Id St Int Rpt
AGCRGSLCCCCRW CLC6_HUMAN 2 2 -
AGCRGSLCCCCRW Q99429 2 2 -
AGCRGSLCCCCRW Q99428 2 2 -
AGCRGSLCCCCRW Q99427 2 2 -
AGCRGSVCCCCRW CLC6_MOUSE 2 2 -

Motif 2 width=10
Element Seqn Id St Int Rpt
AVKWMVVFAI CLC6_HUMAN 78 63 -
AVKWMVVFAI Q99429 78 63 -
AVKWMVVFAI Q99428 78 63 -
AVKWMVVFAI Q99427 78 63 -
AVKWMVVFAI CLC6_MOUSE 78 63 -

Motif 3 width=13
Element Seqn Id St Int Rpt
VDFFVRLFTQLKF CLC6_HUMAN 98 10 -
VDFFVRLFTQLKF Q99429 98 10 -
VDFFVRLFTQLKF Q99428 98 10 -
VDFFVRLFTQLKF Q99427 98 10 -
VDFSVRLFTQLKF CLC6_MOUSE 98 10 -

Motif 4 width=10
Element Seqn Id St Int Rpt
MIHSGSVVGA CLC6_HUMAN 203 92 -
MIHSGSVVGA Q99429 203 92 -
MIHSGSVVGA Q99428 203 92 -
MIHSGSVVGA Q99427 203 92 -
MIHSGAVVGA CLC6_MOUSE 203 92 -

Motif 5 width=10
Element Seqn Id St Int Rpt
LPQFQSISLR CLC6_HUMAN 214 1 -
LPQFQSISLR Q99429 214 1 -
LPQFQSISLR Q99428 214 1 -
LPQFQSISLR Q99427 214 1 -
LPQFQSISLR CLC6_MOUSE 214 1 -