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PR01561

Identifier
EDG8RECEPTOR  [View Relations]  [View Alignment]  
Accession
PR01561
No. of Motifs
10
Creation Date
16-AUG-2001
Title
EDG-8 sphingosine 1-phosphate receptor signature
Database References
PRINTS; PR90007 7TM; PR90006 GPCRCLAN; PR00237 GPCRRHODOPSN
PRINTS; PR01523 S1PRECEPTOR
Literature References
1. ATTWOOD, T.K. AND FINDLAY, J.B.C. 
Fingerprinting G protein-coupled receptors.
PROTEIN ENG. 7(2) 195-203 (1994).
 
2. ATTWOOD, T.K. AND FINDLAY, J.B.C. 
G protein-coupled receptor fingerprints.
7TM, VOLUME 2, EDS. G.VRIEND AND B.BYWATER (1993).
 
3. BIRNBAUMER, L.
G proteins in signal transduction.
ANNU.REV.PHARMACOL.TOXICOL. 30 675-705 (1990).
 
4. CASEY, P.J. AND GILMAN, A.G.
G protein involvement in receptor-effector coupling.
J.BIOL.CHEM. 263(6) 2577-2580 (1988).
 
5. ATTWOOD, T.K. AND FINDLAY, J.B.C. 
Design of a discriminating fingerprint for G protein-coupled receptors.
PROTEIN ENG. 6(2) 167-176 (1993).
 
6. FUKUSHIMA, N., ISHII, I., CONTOS, J.J.A., WEINER, J.A. AND CHUN, J.
Lysophospholipid receptors.
ANNU.REV.PHARMACOL.TOXICOL. 41 507-534 (2001).
 
7. LYNCH, K.R. AND IM, D.-S.
Life on the edg.
TRENDS PHARMACOL.SCI. 20(12) 473-475 (1999).
 
8. PYNE, S. AND PYNE, N.J.
Sphingosine 1-phosphate signalling via the endothelial differentiation gene
family of G-protein-coupled receptors.
PHARMACOL.THER. 88(2) 115-131 (2000).
 
9. MALEK, R.L., TOMAN, R.E., EDSALL, L.C., WONG, S., CHIN, J., LETTERLE,
C.A., VAN BROCKLYN, J.R., MILSTIEN, S., SPIEGEL, S. AND LEE, N.H.
Nrg-1 belongs to the endothelial differentiation gene family of G
protein-coupled sphingosine-1-phosphate receptors.
J.BIOL.CHEM. 276(8) 5692-5699 (2001).

Documentation
G-protein-coupled receptors (GPCRs) constitute a vast protein family that
encompasses a wide range of functions (including various autocrine,
para-crine and endocrine processes). They show considerable diversity at the
sequence level, on the basis of which they can be separated into distinct
groups. We use the term clan to describe the GPCRs, as they embrace a group
of families for which there are indications of evolutionary relationship,
but between which there is no statistically significant similarity in
sequence [1]. The currently known clan members include the rhodopsin-like
GPCRs, the secretin-like GPCRs, the cAMP receptors, the fungal mating
pheromone receptors, and the metabotropic glutamate receptor family.
 
The rhodopsin-like GPCRs themselves represent a widespread protein family
that includes hormone, neurotransmitter and light receptors, all of which
transduce extracellular signals through interaction with guanine
nucleotide-binding (G) proteins. Although their activating ligands vary
widely in structure and character, the amino acid sequences of the receptors
are very similar and are believed to adopt a common structural framework
comprising 7 transmembrane (TM) helices [3-5].
 
Lysophospholipids (LPs), such as lysophosphatidic acid (LPA), sphingosine
1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), have long been
known to act as signalling molecules in addition to their roles as
intermediates in membrane biosynthesis [6]. They have roles in the
regulation of cell growth, differentiation, apoptosis and development, and
have been implicated in a wide range of pathophysiological conditions,
including: blood clotting, corneal wounding, subarachinoid haemorrhage,
inflammation and colitis [7]. A number of G-protein-coupled receptors bind
members of the lysophopholipid family. These include: the cannabinoid
receptors; platelet activating factor receptor; OGR1, an SPC receptor
identified in ovarian cancer cell lines; PSP24, an orphan receptor that has
been proposed to bind LPA; and at least 8 closely related receptors, the EDG
family, that bind LPA and S1P [6].
 
S1P is released from activated platelets and is also produced by a number
of other cell types in response to growth factors and cytokines [8]. It is
proposed to act both as an extracellular mediator and as an intracellular
second messenger. The cellular effects of S1P include growth related
effects, such as proliferation, differentiation, cell survival and
apoptosis, and cytoskeletal effects, such as chemotaxis, aggregation,
adhesion, morphological change and secretion. The molecule has been
implicated in control of angiogenesis, inflammation, heart-rate and tumour
progression and may play an important role in a number of disease states
such as atherosclerosis and breast and ovarian cancer [8]. Recently, 5
G protein-coupled receptors have been identified that act as high affinity
receptors for S1P and also as low affinity receptors for the related
lysophospholipid, SPC [6]. EDG-1, EDG-3, EDG-5 and EDG-8 share a high degree
of similarity and are also referred to as lpB1, lpB3, lpB2 and lpB4,
respectively. EDG-6 is referred to as lpC1, reflecting its more distant
relationship to the other S1P receptors [6].
 
EDG-8 is expressed predominantly in the white matter tracts of the brain and
in the pancreas [8]. Upon binding of S1P, EDG-8 appears to couple to Gi and
G12 proteins but not Gq family members. Unlike other EDG receptors, which 
activate MAP kinases and stimulate proliferation, EDG-8 causes inhibition 
of ERK MAP kinases and proliferation, and also inhibition of adenylyl 
cyclase [9].
 
EDG8RECEPTOR is a 10-element fingerprint that provides a signature for the
EDG-8 sphingosine 1-phosphate receptors. The fingerprint was derived from an
initial alignment of 3 sequences: the motifs were drawn from conserved
sections within N- and C-terminal and loop regions, focusing on those areas
of the alignment that characterise the EDG-8 receptors but distinguish them
from the rest of the sphingosine 1-phosphate receptor family - motif 1
resides at the N-terminus; motif 2 also lies at the N-terminus, leading into
TM domain 1; motif 3 encodes the first cytoplasmic loop; motif 4 spans the
second cytoplasmic loop, leading into TM domain 4; motifs 5 and 6 lie in the
third cytoplasmic loop; and motifs 7-10 reside at the C-terminus. A single
iteration on SPTR39.22_17.3f was required to reach convergence, no further
sequences being identified beyond the starting set.
Summary Information
3 codes involving 10 elements
0 codes involving 9 elements
0 codes involving 8 elements
0 codes involving 7 elements
0 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
103333333333
90000000000
80000000000
70000000000
60000000000
50000000000
40000000000
30000000000
20000000000
12345678910
True Positives
Q9H228        Q9JKM5        Q9QY79        
Sequence Titles
Q9H228      SPHINGOSINE 1-PHOSPHATE RECEPTOR EDG-8 - Homo sapiens (Human). 
Q9JKM5 SPHINGOSINE 1-PHOSPHATE RECEPTOR EDG-8 - Rattus norvegicus (Rat).
Q9QY79 GROWTH FACTOR-REGULATED G PROTEIN-COUPLED RECEPTOR NRG-1 - Rattus norvegicus (Rat).
Scan History
SPTR39.22_17.3f 1  120  NSINGLE    
Initial Motifs
Motif 1  width=16
Element Seqn Id St Int Rpt
MESGLLRPAPVSEVIV Q9JKM5 1 1 -
MESGLLRPAPVSEVIV Q9QY79 1 1 -
MESGLLRPAPVSEVIV Q9H228 1 1 -

Motif 2 width=16
Element Seqn Id St Int Rpt
LRGARYQPGAGLRADA Q9JKM5 25 8 -
LRGARYQPGAGLRADA Q9QY79 25 8 -
LRGARYQPGAGLRADA Q9H228 25 8 -

Motif 3 width=11
Element Seqn Id St Int Rpt
GRHPRFHAPMF Q9JKM5 62 21 -
GRHPRFHAPMF Q9QY79 62 21 -
GRHPRFHAPMF Q9H228 62 21 -

Motif 4 width=15
Element Seqn Id St Int Rpt
RGPAPAASRARTLAM Q9JKM5 140 67 -
RGPAPAASRARTLAM Q9QY79 140 67 -
RGPAPVSSRGRTLAM Q9H228 140 67 -

Motif 5 width=13
Element Seqn Id St Int Rpt
RANARRLRAGPGS Q9JKM5 220 65 -
RANARRLRAGPGS Q9QY79 220 65 -
RANARRLPARPGT Q9H228 220 65 -

Motif 6 width=11
Element Seqn Id St Int Rpt
ATSSSRSRHTP Q9JKM5 235 2 -
ATSSSRSRHTP Q9QY79 235 2 -
GTTSTRARRKP Q9H228 234 1 -

Motif 7 width=12
Element Seqn Id St Int Rpt
GRGPCNQDSSNS Q9JKM5 325 79 -
GRGPCNQDSSNS Q9QY79 325 79 -
GRHSCGRDPSGS Q9H228 324 79 -

Motif 8 width=12
Element Seqn Id St Int Rpt
QRSPSAVGPSGG Q9JKM5 338 1 -
QRSPSAVGPSGG Q9QY79 338 1 -
QQSASAAEASGG Q9H228 336 0 -

Motif 9 width=23
Element Seqn Id St Int Rpt
LRRCLPPTLDRSSSPSEHSCPQR Q9JKM5 351 1 -
LRRCLPPTLDRSSSPSEHSCPQR Q9QY79 351 1 -
LRRCLPPGLDGSFSGSERSSPQR Q9H228 348 0 -

Motif 10 width=22
Element Seqn Id St Int Rpt
DGMDTSCSTGSPGAATANRTLV Q9JKM5 374 0 -
DGMDTSCSTGSPGAATANRTLV Q9QY79 374 0 -
DGLDTSGSTGSPGAPTAARTLV Q9H228 371 0 -
Final Motifs
Motif 1  width=16
Element Seqn Id St Int Rpt
MESGLLRPAPVSEVIV Q9JKM5 1 1 -
MESGLLRPAPVSEVIV Q9QY79 1 1 -
MESGLLRPAPVSEVIV Q9H228 1 1 -

Motif 2 width=16
Element Seqn Id St Int Rpt
LRGARYQPGAGLRADA Q9JKM5 25 8 -
LRGARYQPGAGLRADA Q9QY79 25 8 -
LRGARYQPGAGLRADA Q9H228 25 8 -

Motif 3 width=11
Element Seqn Id St Int Rpt
GRHPRFHAPMF Q9JKM5 62 21 -
GRHPRFHAPMF Q9QY79 62 21 -
GRHPRFHAPMF Q9H228 62 21 -

Motif 4 width=15
Element Seqn Id St Int Rpt
RGPAPAASRARTLAM Q9JKM5 140 67 -
RGPAPAASRARTLAM Q9QY79 140 67 -
RGPAPVSSRGRTLAM Q9H228 140 67 -

Motif 5 width=13
Element Seqn Id St Int Rpt
RANARRLRAGPGS Q9JKM5 220 65 -
RANARRLRAGPGS Q9QY79 220 65 -
RANARRLPARPGT Q9H228 220 65 -

Motif 6 width=11
Element Seqn Id St Int Rpt
ATSSSRSRHTP Q9JKM5 235 2 -
ATSSSRSRHTP Q9QY79 235 2 -
GTTSTRARRKP Q9H228 234 1 -

Motif 7 width=12
Element Seqn Id St Int Rpt
GRGPCNQDSSNS Q9JKM5 325 79 -
GRGPCNQDSSNS Q9QY79 325 79 -
GRHSCGRDPSGS Q9H228 324 79 -

Motif 8 width=12
Element Seqn Id St Int Rpt
QRSPSAVGPSGG Q9JKM5 338 1 -
QRSPSAVGPSGG Q9QY79 338 1 -
QQSASAAEASGG Q9H228 336 0 -

Motif 9 width=23
Element Seqn Id St Int Rpt
LRRCLPPTLDRSSSPSEHSCPQR Q9JKM5 351 1 -
LRRCLPPTLDRSSSPSEHSCPQR Q9QY79 351 1 -
LRRCLPPGLDGSFSGSERSSPQR Q9H228 348 0 -

Motif 10 width=22
Element Seqn Id St Int Rpt
DGMDTSCSTGSPGAATANRTLV Q9JKM5 374 0 -
DGMDTSCSTGSPGAATANRTLV Q9QY79 374 0 -
DGLDTSGSTGSPGAPTAARTLV Q9H228 371 0 -