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PR01113

Identifier
CLCHANNEL2  [View Relations]  [View Alignment]  
Accession
PR01113
No. of Motifs
5
Creation Date
26-APR-1999
Title
CLC-2 chloride channel signature
Database References
PRINTS; PR00762 CLCHANNEL
PRODOM; PD009583
INTERPRO; IPR002244
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. GRUNDER, S., THIEMANN, A., PUSCH, M. AND JENTSCH, T.J.
Regions involved in the opening of ClC-2 chloride channel by voltage and
cell volume.
NATURE 360 759-762 (1992).

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-2 is a member of the CLC family that is ubiquitously expressed in
mammalian tissues. It is 898 amino acid residues in length (human isoform)
and shows ~50% amino acid identity to CLC-1, to which it is most closely
related [1]. The channel is normally closed at physiological membrane 
potentials, but can be activated by rather strong hyperpolarisation. 
However, it is activated by cell swelling, suggesting a role for it in cell
volume regulation. It is also activated by acidic extracellular pH; the
region of the molecule (near the N-terminus) that imparts sensitivity to 
both cell swelling and extracellular pH has been elucidated [6].
 
CLCHANNEL2 is a 5-element fingerprint that provides a signature for the
CLC-2 voltage-gated Cl- channel. The fingerprint was derived from an initial
alignment of 3 sequences: the motifs were drawn from conserved regions
within the N-terminal half of the alignment, focusing on those sections
that characterise the CLC-2 isoform but distinguish it from others -
motifs 1-3 reside within the putative cytoplasmic N-terminus; and motifs 4
and 5 lie within the second and ninth hydrophilic domains, respectively.
Two iterations on SPTR37_9f were required to reach convergence, at which
point a true set comprising 7 sequences was identified.
Summary Information
7 codes involving  5 elements
0 codes involving 4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
577777
400000
300000
200000
12345
True Positives
CLC2_HUMAN    CLC2_RABIT    CLC2_RAT      O14864        
O54821 O54822 O54823
Sequence Titles
CLC2_HUMAN  CHLORIDE CHANNEL PROTEIN 2 (CLC-2) - HOMO SAPIENS (HUMAN). 
CLC2_RABIT CHLORIDE CHANNEL PROTEIN 2 (CLC-2) (PKA-ACTIVATED CHLORIDE CHANNEL) - ORYCTOLAGUS CUNICULUS (RABBIT).
CLC2_RAT CHLORIDE CHANNEL PROTEIN 2 (CLC-2) - RATTUS NORVEGICUS (RAT).
O14864 CHLORIDE CHANNEL PROTEIN - HOMO SAPIENS (HUMAN).
O54821 CHLORIDE CHANNEL 2 - RATTUS NORVEGICUS (RAT).
O54822 CHLORIDE CHANNEL 2 - RATTUS NORVEGICUS (RAT).
O54823 CHLORIDE CHANNEL 2 - RATTUS NORVEGICUS (RAT).
Scan History
SPTR37_9f  2  300  NSINGLE    
Initial Motifs
Motif 1  width=11
Element Seqn Id St Int Rpt
EQTLMYGRYTQ CLC2_RAT 24 24 -
EQTLMYGRYTQ CLC2_HUMAN 18 18 -
EQTLMYGRYTQ CLC2_RABIT 21 21 -

Motif 2 width=10
Element Seqn Id St Int Rpt
LGAFAKEEAA CLC2_RAT 36 1 -
LGAFAKEEAA CLC2_HUMAN 30 1 -
LGAFAKEEAA CLC2_RABIT 33 1 -

Motif 3 width=10
Element Seqn Id St Int Rpt
PSARATPELL CLC2_RAT 59 13 -
PSSRAAPELL CLC2_HUMAN 53 13 -
PSPRTPPELL CLC2_RABIT 56 13 -

Motif 4 width=8
Element Seqn Id St Int Rpt
RGLNTNIL CLC2_RAT 130 61 -
RGLNTSIL CLC2_HUMAN 124 61 -
RGLNTNLL CLC2_RABIT 127 61 -

Motif 5 width=11
Element Seqn Id St Int Rpt
RQGLVEDLGAP CLC2_RAT 414 276 -
RQGLVEELEPP CLC2_HUMAN 408 276 -
RQGLVEELEPP CLC2_RABIT 411 276 -
Final Motifs
Motif 1  width=11
Element Seqn Id St Int Rpt
EQTLMYGRYTQ CLC2_RAT 24 24 -
EQTLMYGRYTQ O54821 24 24 -
EQTLMYGRYTQ O54823 24 24 -
EQTLMYGRYTQ O54822 24 24 -
EQTLMYGRYTQ CLC2_HUMAN 18 18 -
EQTLMYGRYTQ O14864 18 18 -
EQTLMYGRYTQ CLC2_RABIT 21 21 -

Motif 2 width=10
Element Seqn Id St Int Rpt
LGAFAKEEAA CLC2_RAT 36 1 -
LGAFAKEEAA O54821 36 1 -
LGAFAKEEAA O54823 36 1 -
LGAFAKEEAA O54822 36 1 -
LGAFAKEEAA CLC2_HUMAN 30 1 -
LGAFAKEEAA O14864 30 1 -
LGAFAKEEAA CLC2_RABIT 33 1 -

Motif 3 width=10
Element Seqn Id St Int Rpt
PSARATPELL CLC2_RAT 59 13 -
PSARATPDLL O54821 59 13 -
PSARATPDLL O54823 59 13 -
PSARATPDLL O54822 59 13 -
PSSRAAPELL CLC2_HUMAN 53 13 -
PSSRAAPELL O14864 53 13 -
PSPRTPPELL CLC2_RABIT 56 13 -

Motif 4 width=8
Element Seqn Id St Int Rpt
RGLNTNIL CLC2_RAT 130 61 -
RGLNTNIL O54821 130 61 -
RGLNTNIL O54823 130 61 -
RGLNTNIL O54822 130 61 -
RGLNTSIL CLC2_HUMAN 124 61 -
RGLNTSIL O14864 124 61 -
RGLNTNLL CLC2_RABIT 127 61 -

Motif 5 width=11
Element Seqn Id St Int Rpt
RQGLVEDLGAP CLC2_RAT 414 276 -
RQGLVEDLGAP O54821 414 276 -
RQGLVEDLGAP O54823 414 276 -
RQGLVEDLGAP O54822 414 276 -
RQGLVEELEPP CLC2_HUMAN 408 276 -
RQGLVEELEPP O14864 408 276 -
RQGLVEELEPP CLC2_RABIT 411 276 -