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PR01767

Identifier
ECACCHANNEL2  [View Relations]  [View Alignment]  
Accession
PR01767
No. of Motifs
4
Creation Date
26-SEP-2002
Title
Epithelial calcium channel 2 (ECAC2) family signature
Database References
PRINTS; PR01765 ECACCHANNEL
Literature References
1. ZHU, X., JIANG, M., PEYTON, M., BOULAY, G., HURST, R., STEFANI, E. AND
BIRNBAUMER, L. 
Trp, a novel mammalian gene family essential for agonist-activated 
capacitative Ca2+ entry.
CELL 85 661-671 (1996).
 
2. BOULAY, G., ZHU, X., PEYTON, M., JIANG, M., HURST, R., STEFANI, E. AND
BIRNBAUMER, L.
Cloning and expression of a novel mammalian homolog of Drosophila transient 
receptor potential (Trp) involved in calcium entry secondary to activation 
of receptors coupled by the Gq class of G protein.
J.BIOL.CHEM. 272 29672-29680 (1997).
 
3. GUNTHORPE, M.J., BENHAM, C.D., RANDALL, A. AND DAVIS, J.B.
The diversity in the vanilloid (TRPV) receptor family of ion channels.
TRENDS PHARMACOL.SCI. 23(4) 183-191 (2002).
 
4. HOENDEROP, J.G.J., VAN DER KEMP, A.W.C.M., HARTOG, A., VAN OS, C.H.,
WILLEMS, P.H.G.M. AND BINDELS R.J.M.
The epithelial calcium channel, ECaC, is activated by hyperpolarisation and
regulated by cytosolic calcium.
BIOCHEM.BIOPHYS.RES.COMMUM. 261 488-492 (1999).
 
5. BARLEY, N.F., HOWARD, A., O'CALLAGHAN, D., LEGON, S. AND WALTERS, J.R.F.
Epithelial calcium transporter expression in human duodenum.
AM.J.PHYSIOL.GASTROINTEST.LIVER PHYSIOL. 280(2) G285-290 (2001).
 
6. PENG, J.B., CHEN, X.Z., BERGER, U.V., VASSILEV, P.M., TSUKAGUCHI, H.,
BROWN, E.M. AND HEDIGER, M.A.
Molecular cloning and characterization of a channel-like transporter
mediating intestinal calcium absorption.
J.BIOL.CHEM. 274 22739-22746 (1999).
 
7. PAREKH, A.B. AND PENNER, R.
Store depletion and calcium influx.
PHYSIOL.REV. 77 901-930 (1997).
 
8. WISSENBACH, U., NIEMEYER, B.A., FIXEMER, T., SCHNEIDEWIND, A., TROST, C.,
CAVALIE, A., REUS, K., MEESE, E., BONKHOFF, H. AND FLOCKERZI, V.
Expression of CaT-like, a novel calcium-selective channel, correlates with
the malignancy of prostate cancer.
J.BIOL.CHEM. 276 19461-19468 (2001).

Documentation
Transient receptor potential (Trp) and related proteins are thought to be
Ca2+ ion channel subunits that mediate capacitative Ca2+ entry in response 
to a range of external and internal cell stimuli. Such Ca2+ entry is thought 
to be an essential component of cellular responses to many hormones and
growth factors, and acts to replenish intracellular Ca2+ stores that have
been emptied through the action of inositol triphosphate (IP3) and other 
agents. In non-excitable cells (i.e., those that lack voltage-gated Ca2+
channels, such as hepatocytes), this mode of Ca2+ entry is thought to be an
important step in generating the oscillations of intracellular Ca2+
concentration that characterise their response to stimulatory agents [1].
 
Studies on the visual transduction system in Drosophila led to the molecular
cloning of Trp and of a related protein, Trp-like, which show similarity to 
voltage-gated Ca2+ channels in the regions known as S3-S6, including the S5-
S6 linker, which forms the ion-selective channel pore [2]. This provided 
evidence that Trp and/or related proteins might form mammalian capacitative 
Ca2+ entry channels. The sequences of these proteins have varying lengths 
(usually 800-1000 amino acid residues), and hydropathy plots suggest they 
have 6 or more transmembrane (TM) domains, flanked by cytosolic N- and C-
termini. In addition, most contain N-terminal ankyrin repeats [2,3].
 
Following the cloning of the vanilloid receptor (VR1), at least 4 other
related proteins have been identified. Together, these form a distinct
subgroup of the Trp family. Members of the vanilloid receptor family (TRPV)
are activated by a diverse range of stimuli, including heat, protons,
lipids, phorbols, phosphorylation, changes in extracellular osmolarity
and/or pressure, and depletion of intracellular calcium stores [3]. To date,
2 vanilloid receptor-like proteins (VRL-1 and VRL-2) and at least 2 
epithelial calcium channels (ECAC) have been reported.
 
The cloning of ECAC1 (also known as ECAC or CaT2) [4] and ECAC2 (CaT1) [5]
revealed proteins distantly related to VRL. They are highly selective for
calcium and are constitutively active, which gives them an appearance of
calcium-transporter proteins under experimental conditions. They are
important in cellular calcium homeostasis and are tightly regulated by
intracellular and extracellular calcium, which cause channel inactivation
and block respectively [3].
 
ECAC2 was first isolated from rat duodenum using an expression cloning
system [6] and, subsequently, from human small intestine. Its functional
role is similar to ECAC1, being involved in response to a reduction in
calcium. However, as its tissue distribution differs, the consequences of
malfunction are likely to be different. ECAC2 appears to form the Icrac ion
channel, which has a pivotal role in maintenance and regulation of calcium. 
This means that ECAC2 is implicated in processes as diverse as exocytosis, 
enzyme regulation, apoptosis and cell proliferation [7]. More specifically, 
the classic descriptions of Icrac in T-cells predict that antagonists to 
this channel should be useful in treating inflammatory diseases and in 
immunomodulation. It is also potentially involved in cell proliferation, 
and may be linked to human cancer [8].
 
ECACCHANNEL2 is a 4-element fingerprint that provides a signature for the
epithelial calcium channel 2 (ECAC2) family. The fingerprint was derived
from an initial alignment of 3 sequences: the motifs were drawn from 
conserved regions spanning the C-terminal portion of the alignment - motif 1 
encodes the N-terminus of the pore-domain; and motifs 2-4 span the C-
terminus. Two iterations on SPTR40_20f were required to reach convergence, 
at which point a true set comprising 4 sequences was identified.
Summary Information
4 codes involving  4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
44444
30000
20000
1234
True Positives
Q9JIP0        Q9JJL2        Q9NQA5        Q9XSM3        
Sequence Titles
Q9JIP0      CALCIUM TRANSPORTER CAT2 - Rattus norvegicus (Rat). 
Q9JJL2 EPITHELIAL CALCIUM CHANNEL - Rattus norvegicus (Rat).
Q9NQA5 EPITHELIAL CALCIUM CHANNEL (CALCIUM TRANSPORT PROTEIN CAT2) - Homo sapiens (Human).
Q9XSM3 EPITHELIAL CALCIUM CHANNEL - Oryctolagus cuniculus (Rabbit).
Scan History
SPTR40_20f 2  100  NSINGLE    
Initial Motifs
Motif 1  width=13
Element Seqn Id St Int Rpt
EDPESLGEFSDYP Q9JIP0 508 508 -
EDPESLGEFSDYP Q9JJL2 508 508 -
EDPNNLGEFSDYP Q9XSM3 515 515 -

Motif 2 width=18
Element Seqn Id St Int Rpt
QNPYRVLRYVEAFKSSDK Q9JIP0 632 111 -
QNPYRVLRYVEAFKSSDK Q9JJL2 632 111 -
QNPLRVLRYVEAFKCSDK Q9XSM3 639 111 -

Motif 3 width=29
Element Seqn Id St Int Rpt
KEEVQEQLSEKQPSGTETGTLARGSVVLQ Q9JIP0 649 -1 -
KEEVQEQLSEKQPSGTETGTLARGSVVLQ Q9JJL2 649 -1 -
KEDGQEQLSEKRPSTVESGMLSRASVAFQ Q9XSM3 656 -1 -

Motif 4 width=28
Element Seqn Id St Int Rpt
TPPLSRTTSLSSNSHRGWEILRRNTLGH Q9JIP0 678 0 -
TPPLSRTTSLSSNSHRGWEILRRNTLGH Q9JJL2 678 0 -
TPSLSRTTSQSSNSHRGWEILRRNTLGH Q9XSM3 685 0 -
Final Motifs
Motif 1  width=13
Element Seqn Id St Int Rpt
EDPESLGEFSDYP Q9JIP0 508 508 -
EDPESLGEFSDYP Q9JJL2 508 508 -
EDPNNLGEFSDYP Q9XSM3 515 515 -
EDPTSLGQFYDYP Q9NQA5 515 515 -

Motif 2 width=18
Element Seqn Id St Int Rpt
QNPYRVLRYVEAFKSSDK Q9JIP0 632 111 -
QNPYRVLRYVEAFKSSDK Q9JJL2 632 111 -
QNPLRVLRYVEAFKCSDK Q9XSM3 639 111 -
QNPLRVLRYVEVFKNSDK Q9NQA5 639 111 -

Motif 3 width=29
Element Seqn Id St Int Rpt
KEEVQEQLSEKQPSGTETGTLARGSVVLQ Q9JIP0 649 -1 -
KEEVQEQLSEKQPSGTETGTLARGSVVLQ Q9JJL2 649 -1 -
KEDGQEQLSEKRPSTVESGMLSRASVAFQ Q9XSM3 656 -1 -
KEDDQEHPSEKQPSGAESGTLARASLALP Q9NQA5 656 -1 -

Motif 4 width=28
Element Seqn Id St Int Rpt
TPPLSRTTSLSSNSHRGWEILRRNTLGH Q9JIP0 678 0 -
TPPLSRTTSLSSNSHRGWEILRRNTLGH Q9JJL2 678 0 -
TPSLSRTTSQSSNSHRGWEILRRNTLGH Q9XSM3 685 0 -
PTSSLSRTASQSSSHRGWEILRQNTLGH Q9NQA5 684 -1 -