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PR01207

Identifier
NAKCLTRNSPRT  [View Relations]  [View Alignment]  
Accession
PR01207
No. of Motifs
3
Creation Date
15-APR-1999
Title
Na-K-Cl co-transporter family signature
Database References
PRINTS; PR01208 NAKCLTRSPRT1; PR01209 NAKCLTRSPRT2
PRODOM; PD007490
INTERPRO; IPR002443
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).

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].
 
NAKCLTRNSPRT is a 3-element fingerprint that provides a signature for
Na-K-Cl co-transporters. The fingerprint was derived from an initial
alignment of 6 sequences: the motifs were drawn from conserved regions
within the N-terminal ~2/3 of the alignment - motif 1 resides within the 
putative cytoplasmic N-terminus; and motifs 2 and 3 lie within the fourth
and fifth presumed extracellular domains, respectively. Two iterations on
SPTR37_9f were required to reach convergence, at which point a true set 
comprising 10 sequences was identified.
Summary Information
10 codes involving  3 elements
0 codes involving 2 elements
Composite Feature Index
3101010
2000
123
True Positives
NKC1_HUMAN    NKC1_MOUSE    NKC1_SQUAC    NKC2_MOUSE    
NKC2_RABIT NKC2_RAT NKCL_MANSE O18978
O35938 Q13621
Sequence Titles
NKC1_HUMAN  BUMETANIDE-SENSITIVE SODIUM-(POTASSIUM)-CHLORIDE COTRANSPORTER 1 (BASOLATERAL NA-K-CL SYMPORTER) - HOMO SAPIENS (HUMAN). 
NKC1_MOUSE BUMETANIDE-SENSITIVE SODIUM-(POTASSIUM)-CHLORIDE COTRANSPORTER 1 (BASOLATERAL NA-K-CL SYMPORTER) - MUS MUSCULUS (MOUSE).
NKC1_SQUAC BUMETANIDE-SENSITIVE SODIUM-(POTASSIUM)-CHLORIDE COTRANSPORTER 1 (NA-K-CL SYMPORTER) (NKCC) - SQUALUS ACANTHIAS (SPINY DOGFISH).
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).
NKCL_MANSE BUMETANIDE-SENSITIVE SODIUM-(POTASSIUM)-CHLORIDE COTRANSPORTER (NA-K-CL SYMPORTER) - MANDUCA SEXTA (TOBACCO HAWKMOTH) (TOBACCO HORNWORM).
O18978 NA-K-CL COTRANSPORTER - BOS TAURUS (BOVINE).
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=9
Element Seqn Id St Int Rpt
FVRGGGAYY NKC2_MOUSE 234 234 -
VVRGGGAYY NKC2_RAT 234 234 -
FVRGGGAYY NKC2_RABIT 238 238 -
FVRGGGAYY NKC1_HUMAN 346 346 -
FVRGGGAYY NKC1_MOUSE 339 339 -
FVRGGGAYY NKC1_SQUAC 318 318 -

Motif 2 width=11
Element Seqn Id St Int Rpt
CQYGLMNNFQV NKC2_MOUSE 471 228 -
CQYGLMNNFQV NKC2_RAT 471 228 -
CQYGLMNNFQV NKC2_RABIT 475 228 -
CSYGLMNNFQV NKC1_HUMAN 582 227 -
CSYGLMNNFQV NKC1_MOUSE 575 227 -
CSYGLMNDFQV NKC1_SQUAC 555 228 -

Motif 3 width=12
Element Seqn Id St Int Rpt
VITYVIELFLYI NKC2_MOUSE 625 143 -
VITYVIELFLYI NKC2_RAT 625 143 -
VITYVIEFFLYI NKC2_RABIT 629 143 -
LLTYVIVLGLYI NKC1_HUMAN 736 143 -
LLTYVIVLGLYI NKC1_MOUSE 729 143 -
LLTNVIVLALYI NKC1_SQUAC 709 143 -
Final Motifs
Motif 1  width=9
Element Seqn Id St Int Rpt
FVRGGGAYY NKC2_MOUSE 234 234 -
VVRGGGAYY NKC2_RAT 234 234 -
VVRGGGAYY O35938 234 234 -
FVRGGGAYY NKC2_RABIT 238 238 -
FVRGGGAYY NKC1_HUMAN 346 346 -
FVRGGGAYY O18978 338 338 -
FVRGGGAYY NKC1_MOUSE 339 339 -
VVRGGGAYY Q13621 238 238 -
FVRGGGAYY NKC1_SQUAC 318 318 -
EVKGGGIYY NKCL_MANSE 184 184 -

Motif 2 width=11
Element Seqn Id St Int Rpt
CQYGLMNNFQV NKC2_MOUSE 471 228 -
CQYGLMNNFQV NKC2_RAT 471 228 -
CQYGLMNNFQV O35938 471 228 -
CQYGLMNNFQV NKC2_RABIT 475 228 -
CSYGLMNNFQV NKC1_HUMAN 582 227 -
CSYGLMNNFQV O18978 574 227 -
CSYGLMNNFQV NKC1_MOUSE 575 227 -
CQYGLMNNFQV Q13621 475 228 -
CSYGLMNDFQV NKC1_SQUAC 555 228 -
CEYGLHNSYSV NKCL_MANSE 422 229 -

Motif 3 width=12
Element Seqn Id St Int Rpt
VITYVIELFLYI NKC2_MOUSE 625 143 -
VITYVIELFLYI NKC2_RAT 625 143 -
VITYVIELFLYI O35938 625 143 -
VITYVIEFFLYI NKC2_RABIT 629 143 -
LLTYVIVLGLYI NKC1_HUMAN 736 143 -
LLTYVIVLGLYI O18978 728 143 -
LLTYVIVLGLYI NKC1_MOUSE 729 143 -
VITYVIEFFLYV Q13621 629 143 -
LLTNVIVLALYI NKC1_SQUAC 709 143 -
LVTFAIFFTLYL NKCL_MANSE 576 143 -