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PR01209

Identifier
NAKCLTRSPRT2  [View Relations]  [View Alignment]  
Accession
PR01209
No. of Motifs
6
Creation Date
15-APR-1999
Title
Na-K-Cl co-transporter 2 signature
Database References
PRINTS; PR01207 NAKCLTRNSPRT
PRODOM; PD012800; PD013928
INTERPRO; IPR002445
Literature References
1. PAYNE, J.A. AND FORBUSH, B., III.
Molecular characterization of the epithelial Na-K-Cl cotransporter
isoforms.
CURR.OPIN.CELL BIOL. 7 493-503 (1995).
 
2. SIMON, D.B. AND LIFTON, R.P.
Mutations in Na(K)Cl transporters in Gitelman's and Bartter's syndromes.
CURR.OPIN.CELL BIOL. 10 450-454 (1998).
 
3. GAMBA, G., MIYANOSHITA, A., LOMBARDI, M., LYTTON, J., LEE, W.-S.,
HEDIGER, M.A. AND HEBERT, S.C.
Molecular cloning, primary structure, and characterization of two members
of the mammalian electroneutral sodium-(Potassium)-chloride cotransporter
family expressed in kidney.
J.BIOL.CHEM. 269 17713-17722 (1994).
 
4. PAYNE, J.A. AND FORBUSH, B., III.
Alternatively spliced isoforms of the putative renal Na-K-Cl cotransporter
are differentially distributed within the rat rabbit kidney.
PROC.NATL.ACAD.SCI.U.S.A. 91 4544-4584 (1994).

Documentation
The Na-K-Cl co-transporters are a family of integral membrane proteins that
are ubiquitously expressed in animal tissues, serving a variety of
functions. In cells of Cl- absorptive and Cl- secretory epithelia, Na-K-Cl
co-transport serves as the major Cl- entry pathway, and functions in
concert with other membrane ion channels and pumps to carry out net trans-
epithelial movement of salt. This vectorial transport of Cl- across
epithelia is involved in the reabsorption of salt in the vertebrate kidney
(which is crucial for urinary concentration), and in the secretion of salt
in such tissues as the mammalian intestine and trachea. In addition, 
Na-K-Cl co-transport is known to play a role in cell volume regulation in
most mammalian cell types. The proteins mediate the coupled, electroneutral
transport of sodium, potassium and chloride ions across the plasma membrane
of cells (with a stoichiometry of 1:1:2, respectively). Co-transport of all
three ions is obligatory, since absence of one is sufficient to prevent ion
movement. Their transport activity does not alter the cell's membrane 
potential, thus the driving force for the transport is determined solely
by the chemical gradients of the three transported ions; hence, under
normal physiological conditions, the direction will be inward.
 
Recent molecular studies have identified two distinct isoforms: one from
Cl- secretory epithelia, NKCC1; and another, NKCC2, found specifically in
the diluting segment of the vertebrate kidney, a Cl- absorptive epithelium
[1]. They show lowish amino acid sequence identity (~58%); nevertheless,
they have rather similar hydropathy profiles, with hydrophilic N- and C-
termini, flanking a central hydrophobic domain. Their N-termini show 
considerable variation, unlike the central domain (containing the 12 
putative transmembrane (TM) domains) and their C-termini, which are well
conserved (~70%). Both isoforms are known to be glycosylated and, consistent
with this, consensus sites for N-linked glycosylation are located within the
large hydrophilic loop between presumed TM domains 7 and 8. Sequence
comparisons with other cloned ion co-transporters reveals that Na-K-Cl
co-transporters belong to a superfamily of electroneutral cation-chloride
co-transporters, which includes the K-Cl co-transporter (PR01081) and the
thiazide-sensitive Na-Cl co-transporter. All share a similar predicted
membrane topology of 12 TM regions in a central hydrophobic domain,
together with hydrophilic N- and C-termini that are likely cytoplasmic.
 
Mutations in the gene encoding the renal-specific isoform of the Na-K-Cl
co-transporter (NKCC2) give rise to Bartter's Syndrome Type 1, an inherited 
kidney disease characterised by hypokalaemia, metabolic alkalosis, salt-
wasting and hypotension [2].
 
NKCC2 (also called BSC1) is an apical absorptive Na-K-Cl co-transporter
isoform. In contrast to the wide tissue distribution of NKCC1, expression
of the NKCC2 isoform is restricted to the vertebrate kidney, where it is
involved in urinary concentration [3]. Subsequent studies revealed that
three variants exist, differing by 31 amino acids, which are generated
by alternatively splicing. They show differential distributions within
the kidney, suggesting they may subserve varying functions [4]. NKCC2
consists of 1099 amino acid residues (human isoform) and, as mentioned
above, has been found to be responsible for a heritable kidney disorder,
Bartter's syndrome type 1, an autosomal recessive disorder. To date, at
least six different mutations have been found that result in loss of
NKCC2 function; this markedly reduces salt reabsorption by the thick
ascending limb of Henle's loop, thereby leading to salt wasting, hypo-
volaemia, and hypotension [2].
 
NAKCLTRSPRT2 is a 6-element fingerprint that provides a signature for the
Na-K-Cl co-transporter type 2 isoform. The fingerprint was derived from
an initial alignment of 3 sequences: the motifs were drawn from conserved
regions within the first ~2/3 of the alignment, focusing on those sections
that characterise the Na-K-Cl co-transporter type 2 isoform but distinguish
it from others - motifs 1-3 reside within the presumed cytoplasmic
N-terminus; and motifs 4-6 encode portions of the second, fourth and fifth
presumed extracellular domains, respectively. 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  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
6555555
5000000
4000000
3000000
2000000
123456
True Positives
NKC2_MOUSE    NKC2_RABIT    NKC2_RAT      O35938        
Q13621
Sequence Titles
NKC2_MOUSE  BUMETANIDE-SENSITIVE SODIUM-(POTASSIUM)-CHLORIDE COTRANSPORTER 2 (KIDNEY-SPECIFIC NA-K-CL SYMPORTER) - MUS MUSCULUS (MOUSE). 
NKC2_RABIT BUMETANIDE-SENSITIVE SODIUM-(POTASSIUM)-CHLORIDE COTRANSPORTER 2 (KIDNEY-SPECIFIC NA-K-CL SYMPORTER) - ORYCTOLAGUS CUNICULUS (RABBIT).
NKC2_RAT BUMETANIDE-SENSITIVE SODIUM-(POTASSIUM)-CHLORIDE COTRANSPORTER 2 (KIDNEY-SPECIFIC NA-K-CL SYMPORTER) - RATTUS NORVEGICUS (RAT).
O35938 NA-(K)-CL COTRANSPORTER ISOFORM MBSC1-F9 - MUS MUSCULUS (MOUSE).
Q13621 BUMETANIDE-SENSITIVE NA-K-2CL COTRANSPORTER - HOMO SAPIENS (HUMAN).
Scan History
SPTR37_9f  2  300  NSINGLE    
Initial Motifs
Motif 1  width=11
Element Seqn Id St Int Rpt
QNRLRISFRPG NKC2_MOUSE 51 51 -
QNRLRISFRPG NKC2_RABIT 54 54 -
QNRLKISFRPG NKC2_RAT 51 51 -

Motif 2 width=9
Element Seqn Id St Int Rpt
NQECYDNFL NKC2_MOUSE 62 0 -
NQECYDNFL NKC2_RABIT 65 0 -
NQECYENFL NKC2_RAT 62 0 -

Motif 3 width=12
Element Seqn Id St Int Rpt
ADRVANGDGMPG NKC2_MOUSE 145 74 -
ADRVANGEGMPG NKC2_RABIT 148 74 -
ADRVANGDGMPG NKC2_RAT 145 74 -

Motif 4 width=10
Element Seqn Id St Int Rpt
SDSMMVDPTN NKC2_MOUSE 286 129 -
SDSMMVDPTN NKC2_RABIT 290 130 -
SDSMMVDPTN NKC2_RAT 286 129 -

Motif 5 width=11
Element Seqn Id St Int Rpt
TIVSGMNCNGS NKC2_MOUSE 444 148 -
TIISGINCNGS NKC2_RABIT 448 148 -
TVVSGMNCNGS NKC2_RAT 444 148 -

Motif 6 width=11
Element Seqn Id St Int Rpt
SGLCICCEVFV NKC2_MOUSE 704 249 -
SGLCICCEVFV NKC2_RABIT 708 249 -
SGLCICCEVFV NKC2_RAT 704 249 -
Final Motifs
Motif 1  width=11
Element Seqn Id St Int Rpt
QNRLRISFRPG NKC2_MOUSE 51 51 -
QNRLRISFRPG O35938 51 51 -
QKRLRISFRPG Q13621 55 55 -
QNRLRISFRPG NKC2_RABIT 54 54 -
QNRLKISFRPG NKC2_RAT 51 51 -

Motif 2 width=9
Element Seqn Id St Int Rpt
NQECYDNFL NKC2_MOUSE 62 0 -
NQECYDNFL O35938 62 0 -
NQECYDNFL Q13621 66 0 -
NQECYDNFL NKC2_RABIT 65 0 -
NQECYENFL NKC2_RAT 62 0 -

Motif 3 width=12
Element Seqn Id St Int Rpt
ADRVANGDGMPG NKC2_MOUSE 145 74 -
ADRVANGDGMPG O35938 145 74 -
ADRVANGDGIPG Q13621 149 74 -
ADRVANGEGMPG NKC2_RABIT 148 74 -
ADRVANGDGMPG NKC2_RAT 145 74 -

Motif 4 width=10
Element Seqn Id St Int Rpt
SDSMMVDPTN NKC2_MOUSE 286 129 -
SDSMMVDPTN O35938 286 129 -
SDSMMVDPTN Q13621 290 129 -
SDSMMVDPTN NKC2_RABIT 290 130 -
SDSMMVDPTN NKC2_RAT 286 129 -

Motif 5 width=11
Element Seqn Id St Int Rpt
TIVSGMNCNGS NKC2_MOUSE 444 148 -
TIVSGMNCNGS O35938 444 148 -
TIISGMNCNGS Q13621 448 148 -
TIISGINCNGS NKC2_RABIT 448 148 -
TVVSGMNCNGS NKC2_RAT 444 148 -

Motif 6 width=11
Element Seqn Id St Int Rpt
SGLCICCEVFV NKC2_MOUSE 704 249 -
SGLCICCEVFV O35938 704 249 -
SGLCICCEVFV Q13621 708 249 -
SGLCICCEVFV NKC2_RABIT 708 249 -
SGLCICCEVFV NKC2_RAT 704 249 -