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PR01112

Identifier
CLCHANNEL1  [View Relations]  [View Alignment]  
Accession
PR01112
No. of Motifs
7
Creation Date
23-APR-1999
Title
CLC-1 chloride channel signature
Database References
PRINTS; PR00762 CLCHANNEL
PRODOM; PD035113; PD036720; PD036729; PD036731
INTERPRO; IPR002243
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., ORTLAND, C. AND JENTSCH, T.J.
Primary structure and fuctional expression of a developmentally regulated
skeletal muscle chloride channel.
NATURE 354 301-304 (1991).

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-1 was the first member of the CLC family cloned from mammalian species
[6], and has 998 amino acid residues (human isoform). It is principally
expressed in skeletal muscle, but low transcript levels can be detected in
kidney, heart and smooth muscle. In skeletal muscle, it gives rise to the
majority of the muscle membrane Cl- conductance (which accounts for ~70-80%
of the total resting conductance). These channels are partially open under
resting conditions, and it is likely that following a prolonged series of
muscle action potentials, they act to reduce excitability, limiting tetanic
activation. As mentioned above, mutations in CLC-1 can cause recessive
(Becker) as well as dominant (Thomsen) myotonia. Such mutations reduce
channel function, rendering skeletal muscle hyperexcitable. This leads to
defective muscle relaxation after voluntary contraction.
 
CLCHANNEL1 is a 7-element fingerprint that provides a signature for the
CLC-1 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-1 isoform but distinguish it from others -
motifs 1-4 reside within the putative cytoplasmic N-terminus; and motifs
5-7 lie within the 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
2 codes involving  7 elements
0 codes involving 6 elements
0 codes involving 5 elements
0 codes involving 4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
72222222
60000000
50000000
40000000
30000000
20000000
1234567
True Positives
CLC1_HUMAN    CLC1_RAT      
Sequence Titles
CLC1_HUMAN  CHLORIDE CHANNEL PROTEIN, SKELETAL MUSCLE (CHLORIDE CHANNEL PROTEIN 1) (CLC-1) - HOMO SAPIENS (HUMAN). 
CLC1_RAT CHLORIDE CHANNEL PROTEIN, SKELETAL MUSCLE (CHLORIDE CHANNEL PROTEIN 1) (CLC-1) - RATTUS NORVEGICUS (RAT).
Scan History
SPTR37_9f  1  300  NSINGLE    
Initial Motifs
Motif 1  width=12
Element Seqn Id St Int Rpt
SQQRGGEQSWWG CLC1_HUMAN 6 6 -
SQQHGGEQSWWG CLC1_RAT 6 6 -

Motif 2 width=15
Element Seqn Id St Int Rpt
PQYQYMPFEHCTSYG CLC1_HUMAN 20 2 -
PQYQYMPFEHCTSYG CLC1_RAT 20 2 -

Motif 3 width=15
Element Seqn Id St Int Rpt
RKDAGPRHNVHPTQI CLC1_HUMAN 47 12 -
RKDLGPRHNAHPTQI CLC1_RAT 47 12 -

Motif 4 width=13
Element Seqn Id St Int Rpt
GMPKKTGSSSTVD CLC1_HUMAN 77 15 -
GIPKKTDSSSTVD CLC1_RAT 77 15 -

Motif 5 width=8
Element Seqn Id St Int Rpt
RKLSELPY CLC1_HUMAN 679 589 -
RKLSELPY CLC1_RAT 679 589 -

Motif 6 width=14
Element Seqn Id St Int Rpt
DEDEDEDLSGKSEL CLC1_HUMAN 712 25 -
DEDEDEDVSRKTEL CLC1_RAT 709 22 -

Motif 7 width=11
Element Seqn Id St Int Rpt
PETPVPSPSPE CLC1_HUMAN 927 201 -
PETPVPPPSPE CLC1_RAT 933 210 -
Final Motifs
Motif 1  width=12
Element Seqn Id St Int Rpt
SQQRGGEQSWWG CLC1_HUMAN 6 6 -
SQQHGGEQSWWG CLC1_RAT 6 6 -

Motif 2 width=15
Element Seqn Id St Int Rpt
PQYQYMPFEHCTSYG CLC1_HUMAN 20 2 -
PQYQYMPFEHCTSYG CLC1_RAT 20 2 -

Motif 3 width=15
Element Seqn Id St Int Rpt
RKDAGPRHNVHPTQI CLC1_HUMAN 47 12 -
RKDLGPRHNAHPTQI CLC1_RAT 47 12 -

Motif 4 width=13
Element Seqn Id St Int Rpt
GMPKKTGSSSTVD CLC1_HUMAN 77 15 -
GIPKKTDSSSTVD CLC1_RAT 77 15 -

Motif 5 width=8
Element Seqn Id St Int Rpt
RKLSELPY CLC1_HUMAN 679 589 -
RKLSELPY CLC1_RAT 679 589 -

Motif 6 width=14
Element Seqn Id St Int Rpt
DEDEDEDLSGKSEL CLC1_HUMAN 712 25 -
DEDEDEDVSRKTEL CLC1_RAT 709 22 -

Motif 7 width=11
Element Seqn Id St Int Rpt
PETPVPSPSPE CLC1_HUMAN 927 201 -
PETPVPPPSPE CLC1_RAT 933 210 -