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PR01114

Identifier
CLCHANNEL3  [View Relations]  [View Alignment]  
Accession
PR01114
No. of Motifs
5
Creation Date
26-APR-1999
Title
CLC-3 chloride channel signature
Database References
PRINTS; PR00762 CLCHANNEL
INTERPRO; IPR002245
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. BORSANI, G., RUGARLI, E.I., TAGLIALATELA, M., WONG, C. AND BALLABIO, A.
Characterization of a human and murine gene (CLCN3) sharing similarities
to voltage-gated chloride channels and to a yeast integral membrane
protein.
GENOMICS 27 131-141 (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. DUAN, D., WINTER, C., COWLEY, S., HUME, J.R. AND HOROWITZ, B.
Molecular identification of a volume-regulated chloride channel.
NATURE 390 417-421 (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-3 is a member of the CLC family initially cloned from rat kidney [6]
and localised to chromosome 4 in humans [7]; the human isoform contains 762
amino acid residues. Together with CLC-4 and CLC-5, it forms a distinct 
branch of the CLC gene family, the three members showing ~80% residue
identity. Expression of CLC-3 produces outwardly-rectifying Cl- currents
that are inhibited by protein kinase C activation [6; see 8 for review].
More recently, it has been suggested that CLC-3 may be a ubiquitous swelling
-activated Cl- channel that has very similar characteristics to those of
native volume-regulated Cl- currents [8].
 
CLCHANNEL3 is a 5-element fingerprint that provides a signature for the
CLC-3 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-3 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 6 sequences was identified.
Summary Information
6 codes involving  5 elements
0 codes involving 4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
566666
400000
300000
200000
12345
True Positives
CLC3_HUMAN    CLC3_MOUSE    CLC3_RAT      O14918        
O18894 P97274
Sequence Titles
CLC3_HUMAN  CHLORIDE CHANNEL PROTEIN 3 (CLC-3) - HOMO SAPIENS (HUMAN). 
CLC3_MOUSE CHLORIDE CHANNEL PROTEIN 3 (CLC-3) - MUS MUSCULUS (MOUSE).
CLC3_RAT CHLORIDE CHANNEL PROTEIN 3 (CLC-3) - RATTUS NORVEGICUS (RAT).
O14918 CHLORIDE CHANNEL PROTEIN 3 - HOMO SAPIENS (HUMAN).
O18894 CHLORIDE CHANNEL PROTEIN 3 - ORYCTOLAGUS CUNICULUS (RABBIT).
P97274 VOLUME-REGULATED OUTWARDLY-RECTIFYING CHLORIDE CHANNEL - CAVIA PORCELLUS (GUINEA PIG).
Scan History
SPTR37_9f  2  200  NSINGLE    
Initial Motifs
Motif 1  width=11
Element Seqn Id St Int Rpt
MTNGGSINSST CLC3_HUMAN 1 1 -
MTNGGSINSST CLC3_RAT 1 1 -
MTNGGSINSST CLC3_MOUSE 1 1 -

Motif 2 width=7
Element Seqn Id St Int Rpt
KCKDRER CLC3_HUMAN 39 27 -
KCKDRER CLC3_RAT 39 27 -
KCKDRER CLC3_MOUSE 39 27 -

Motif 3 width=7
Element Seqn Id St Int Rpt
SAWEMTK CLC3_HUMAN 56 10 -
SAWEMTK CLC3_RAT 56 10 -
SAWEMTK CLC3_MOUSE 56 10 -

Motif 4 width=11
Element Seqn Id St Int Rpt
IGQAEGPGSYI CLC3_HUMAN 140 77 -
IGQAEGPGSYI CLC3_RAT 140 77 -
IGQAEGPGSYI CLC3_MOUSE 140 77 -

Motif 5 width=10
Element Seqn Id St Int Rpt
YRNDMNASKI CLC3_HUMAN 416 265 -
YRNDMNASKI CLC3_RAT 416 265 -
YRNDMNASKI CLC3_MOUSE 416 265 -
Final Motifs
Motif 1  width=11
Element Seqn Id St Int Rpt
MTNGGSINSST CLC3_HUMAN 1 1 -
MTNGGSINSST P97274 1 1 -
MTNGGSINSST O18894 59 59 -
MTNGGSINSST O14918 59 59 -
MTNGGSINSST CLC3_RAT 1 1 -
MTNGGSINSST CLC3_MOUSE 1 1 -

Motif 2 width=7
Element Seqn Id St Int Rpt
KCKDRER CLC3_HUMAN 39 27 -
KCKDRER P97274 39 27 -
KCKDRER O18894 97 27 -
KCKDRER O14918 97 27 -
KCKDRER CLC3_RAT 39 27 -
KCKDRER CLC3_MOUSE 39 27 -

Motif 3 width=7
Element Seqn Id St Int Rpt
SAWEMTK CLC3_HUMAN 56 10 -
SAWEMTK P97274 56 10 -
SAWEMTK O18894 114 10 -
SAWEMTK O14918 114 10 -
SAWEMTK CLC3_RAT 56 10 -
SAWEMTK CLC3_MOUSE 56 10 -

Motif 4 width=11
Element Seqn Id St Int Rpt
IGQAEGPGSYI CLC3_HUMAN 140 77 -
IGQAEGPGSYI P97274 140 77 -
IGQAEGPGSYI O18894 198 77 -
IGQAEGPGSYI O14918 198 77 -
IGQAEGPGSYI CLC3_RAT 140 77 -
IGQAEGPGSYI CLC3_MOUSE 140 77 -

Motif 5 width=10
Element Seqn Id St Int Rpt
YRNDMNASKI CLC3_HUMAN 416 265 -
YRNDMNASKI P97274 416 265 -
YRNDMNASKI O18894 474 265 -
YRNDMNASKI O14918 474 265 -
YRNDMNASKI CLC3_RAT 416 265 -
YRNDMNASKI CLC3_MOUSE 416 265 -