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PR01119

Identifier
CLCHANNELKDY  [View Relations]  [View Alignment]  
Accession
PR01119
No. of Motifs
5
Creation Date
27-APR-1999
Title
CLC-K chloride channel family signature
Database References
PRINTS; PR00762 CLCHANNEL
INTERPRO; IPR002250
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. KIEFERLE, S., FONG, P., BENS, M., VANDEWALLE, A. AND JENTSCH, T.J.
Two highly homologous members of the ClC chloride channel family in both
rat and human kidney.
PROC.NATL.ACAD.SCI.U.S.A. 91 6943-6947 (1994).
 
7. ADACHI, S., UCHIDA, S., ITO, H., HATA, M., HIROE, M., MARUMO, F. AND
SASAKI, S.
Two isoforms of a chloride channel predominantly expressed in thick
ascending limb of Henle's loop and collecting ducts of rat kidney.
J.BIOL.CHEM. 269 17677-17683 (1994).
 
8. SIMON, D.B., BINDRA, R.S., MANSFIELD, T.A., NELSON-WILLIAMS, C.,
MENDONCA, E., STONE, R., SCHURMAN, S., NAYIR, A., ALPAY, H.,
BAKKALOGLU, A., RODRIGUEZ-SORIANO, J., MORALES, J.M., SANJAD, S.A.,
TAYLOR, C.M., PILZ, D., BREM, A., TRACHTMAN, H., GRISWOLD, W.,
RICHARD, G.A., JOHN, E. AND LIFTON, R.P.
Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome
type III.
NAT.GENET. 17 171-178 (1997).
 
9. MATSUMURA, Y., UCHIDA, S., KONDO, Y., MIYAZAKI, H., KO, S.B.H., 
HAYAMA, A., MORIMOTO, T., LIU, W., ARISAWA, M., SASAKI, S. AND MARUMO, F.
Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride
channel.
NAT.GENET. 21 95-98 (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.
 
Two highly similar members of the CLC family have been cloned that appear
to be kidney-specific isoforms. These are known as CLC-Ka and CLC-Kb in
humans and are ~90% identical (at the amino acid level); in other species,
they are named CLC-K1 and CLC-K2 [6,7]. Within species, the two isoforms
show differing distribution patterns in the kidney, possibly suggesting
diferent roles in renal function. To date, attempts at functional expression
of CLC-K isoforms have not yielded measurable Cl- currents; however, that
they play a key role in normal kidney function had been made clear by the 
fact that naturally occurring mutations in the human gene CLCNKB (encoding
CLC-Kb) lead to a form of Bartter's syndrome, an inherited kidney disease 
characterised by hypokalaemic alkalosis [8]. Similarly, transgenic mice,
whose CLC-K1 channel has been rendered dysfunctional by targeted gene 
disruption, develop overt diabetes, suggesting that these channels are
important for urinary concentration [9].
 
CLCHANNELKDY is a 5-element fingerprint that provides a signature for the
CLC-K voltage-gated Cl- channel. The fingerprint was derived from an
initial alignment of 5 sequences: the motifs were drawn from conserved
regions within the N-terminal half of the alignment, focusing on those
sections that characterise CLC-K Cl- channel isoforms but distinguish
them from others - motif 1 resides within the putative cytoplasmic
N-terminus; motifs 2 and 3 lie within the third and fourth hydrophobic
domains, respectively; motif 4 encodes the C-terminal portion of the sixth
hydrophobic domain, and leads into the subsequent hydrophilic domain; and
motif 6 lies at the end of the eighth hydrophobic domain, extending into
the following hydrophilic region. 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
CICK_HUMAN    CICK_RABIT    CICK_RAT      CICL_HUMAN    
CICL_RABIT CICL_RAT
Sequence Titles
CICK_HUMAN  CHLORIDE CHANNEL PROTEIN CLC-KA (CLC-K1) - HOMO SAPIENS (HUMAN). 
CICK_RABIT CHLORIDE CHANNEL PROTEIN CLC-K1 - ORYCTOLAGUS CUNICULUS (RABBIT).
CICK_RAT CHLORIDE CHANNEL PROTEIN CLC-K1 - RATTUS NORVEGICUS (RAT).
CICL_HUMAN CHLORIDE CHANNEL PROTEIN CLC-KB (CLC-K2) - HOMO SAPIENS (HUMAN).
CICL_RABIT CHLORIDE CHANNEL PROTEIN CLC-K2 - ORYCTOLAGUS CUNICULUS (RABBIT).
CICL_RAT CHLORIDE CHANNEL PROTEIN CLC-K2 - RATTUS NORVEGICUS (RAT).
Scan History
SPTR37_9f  2  300  NSINGLE    
Initial Motifs
Motif 1  width=7
Element Seqn Id St Int Rpt
PCPRIRR CICK_RAT 24 24 -
PCPRIRR CICL_RAT 24 24 -
PCPRLRR CICK_RABIT 24 24 -
PCPLIRR CICL_HUMAN 24 24 -
PCPHIRR CICK_HUMAN 24 24 -

Motif 2 width=9
Element Seqn Id St Int Rpt
SCTLATGST CICK_RAT 152 121 -
SCTLATGST CICL_RAT 152 121 -
SCTLATGST CICK_RABIT 152 121 -
SCTLACGST CICL_HUMAN 152 121 -
SCTLATGST CICK_HUMAN 152 121 -

Motif 3 width=7
Element Seqn Id St Int Rpt
AYLGRVR CICK_RAT 178 17 -
AYLGRVR CICL_RAT 178 17 -
AYLGRVR CICK_RABIT 178 17 -
AYLGRVR CICL_HUMAN 178 17 -
AYLGRVR CICK_HUMAN 178 17 -

Motif 4 width=7
Element Seqn Id St Int Rpt
FNSEQET CICK_RAT 256 71 -
FNSEQET CICL_RAT 256 71 -
FNSEQET CICK_RABIT 256 71 -
FNSEQET CICL_HUMAN 256 71 -
FNSEQET CICK_HUMAN 256 71 -

Motif 5 width=9
Element Seqn Id St Int Rpt
RFMASRLSM CICK_RAT 346 83 -
RFMASRLSM CICL_RAT 346 83 -
RFMASRLSM CICK_RABIT 346 83 -
RFLASRLSM CICL_HUMAN 346 83 -
HFLASRLSM CICK_HUMAN 346 83 -
Final Motifs
Motif 1  width=7
Element Seqn Id St Int Rpt
PCPRIRR CICK_RAT 24 24 -
PCPRIRR CICL_RAT 24 24 -
PCPRLRR CICK_RABIT 24 24 -
PCPRLRR CICL_RABIT 24 24 -
PCPLIRR CICL_HUMAN 24 24 -
PCPHIRR CICK_HUMAN 24 24 -

Motif 2 width=9
Element Seqn Id St Int Rpt
SCTLATGST CICK_RAT 152 121 -
SCTLATGST CICL_RAT 152 121 -
SCTLATGST CICK_RABIT 152 121 -
SCTLATGST CICL_RABIT 152 121 -
SCTLACGST CICL_HUMAN 152 121 -
SCTLATGST CICK_HUMAN 152 121 -

Motif 3 width=7
Element Seqn Id St Int Rpt
AYLGRVR CICK_RAT 178 17 -
AYLGRVR CICL_RAT 178 17 -
AYLGRVR CICK_RABIT 178 17 -
AYLGRVR CICL_RABIT 178 17 -
AYLGRVR CICL_HUMAN 178 17 -
AYLGRVR CICK_HUMAN 178 17 -

Motif 4 width=7
Element Seqn Id St Int Rpt
FNSEQET CICK_RAT 256 71 -
FNSEQET CICL_RAT 256 71 -
FNSEQET CICK_RABIT 256 71 -
FNSEQET CICL_RABIT 256 71 -
FNSEQET CICL_HUMAN 256 71 -
FNSEQET CICK_HUMAN 256 71 -

Motif 5 width=9
Element Seqn Id St Int Rpt
RFMASRLSM CICK_RAT 346 83 -
RFMASRLSM CICL_RAT 346 83 -
RFMASRLSM CICK_RABIT 346 83 -
RFMASRLSM CICL_RABIT 346 83 -
RFLASRLSM CICL_HUMAN 346 83 -
HFLASRLSM CICK_HUMAN 346 83 -