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PR01147

Identifier
GPR4RECEPTOR  [View Relations]  [View Alignment]  
Accession
PR01147
No. of Motifs
8
Creation Date
14-MAR-1999  (UPDATE 20-DEC-2001)
Title
GPR4 sphingosylphosphorylcholine and lysophosphatidylcholine receptor signature
Database References
PRINTS; PR90007 7TM; PR90006 GPCRCLAN; PR00237 GPCRRHODOPSN
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. XU, Y., ZHU, K., HONG, G., WU, W., BAUDHUIN, L.M., XIAO, Y. AND
DAMRON, D.S.
Sphingosylphosphorylcholine is a ligand for ovarian cancer G-protein-coupled
receptor 1.
NAT.CELL.BIOL. 2(5) 261-267 (2000).
 
9. KABAROWSKI, J.H., ZHU, K., LE, L.Q., WITTE, O.N. AND XU, Y.
Lysophosphatidylcholine as a ligand for the immunoregulatory receptor G2A.
SCIENCE 293 702-705 (2001).
 
10. ZHU, K., BAUDHUIN, L.M., HONG, G., WILLIAMS, F.S., CRISTINA, K.L.,
KABAROWSKI, J.H.S., WITTE, O.N. AND XU, Y.
Sphingosylphosphorylcholine and lysophosphatidylcholine are ligands for the
G protein-coupled receptor GPR4.
J.BIOL.CHEM. 276(44) 41325-41335 (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 lysophospholipid 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]. 
 
SPC is produced from degradation of sphingomyelin and regulates many diverse
cellular functions, such as: proliferation, growth inhibition, smooth muscle
contraction and wound healing [6,8]. It is also thought to play a role in
the cardiovascular system and potently activates inwardly rectifying K+
channels, suggesting a possible role in regulation of heart rate [6].
 
Lysophosphatidylcholine (LPC) is produced by the action of phospholipase A2
on phosphatidylcholine and promotes inflammatory effects, such as monocyte
chemotaxis, increased expression of endothelial cell adhesion molecules and
growth factors, and macrophage activation. LPC also plays a role in
atherosclerosis and has been implicated in the pathogenesis of systemic
lupus erythematosus, an autoimmune disease [9].
 
The orphan receptor GPR4 has been identified as a high affinity receptor for
SPC and a lower affinity receptor for LPC [10]. GPR4 is expressed at highest
levels in the ovary, liver, lung, kidney, lymph nodes and subthalamic
nuclei. Activation of GPR4 mediates an increase in intracellular calcium,
activation of serum response element, ERK kinase activation and stimulation
of cell migration [10].
 
GPR4RECEPTOR is an 8-element fingerprint that provides a signature for the
GPR4 sphingosylphosphorylcholine and lysophosphatidylcholine receptors. The
fingerprint was derived from an initial alignment of 2 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 GPR4
receptors but distinguish them from the rest of the lysophospholipid
receptor family - motif 1 resides at the N-terminus, leading into TM domain
1; motif 2 lies in the second cytoplasmic loop, leading into TM domain 4;
motif 3 spans the C-terminal portion of TM domain 4, leading into the second
external loop; motif 4 lies in the second external loop; motif 5 spans the
third cytoplasmic loop; motif 6 encodes the third external loop; and motifs
7 and 8 reside at the C-terminus. A single iteration on SPTR40_18f was
required to reach convergence, no further sequences being identified beyond
the starting set.
Summary Information
2 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
822222222
700000000
600000000
500000000
400000000
300000000
200000000
12345678
True Positives
GPR4_HUMAN    GPR4_PIG      
Sequence Titles
GPR4_HUMAN  Probable G-protein coupled receptor 4 (G-protein coupled receptor 19) - Homo sapiens (Human). 
GPR4_PIG Probable G-protein coupled receptor 4 (G-protein coupled receptor 19) - Sus scrofa (Pig).
Scan History
SPTR37_9f  1  3    NSINGLE    
SPTR40_18f 1 85 NSINGLE
Initial Motifs
Motif 1  width=22
Element Seqn Id St Int Rpt
MGNHTWEGCHVDSRVDHLFPPS GPR4_HUMAN 1 1 -
MGNGTWEGCHVDSRVDHLFPPS GPR4_PIG 1 1 -

Motif 2 width=13
Element Seqn Id St Int Rpt
RFARLRRVKTAVA GPR4_HUMAN 124 101 -
RFARLRRVKTAVA GPR4_PIG 124 101 -

Motif 3 width=19
Element Seqn Id St Int Rpt
ANSAPLFHDELFRDRYNHT GPR4_HUMAN 148 11 -
ANSVPLFHDELFRDRYNHT GPR4_PIG 148 11 -

Motif 4 width=10
Element Seqn Id St Int Rpt
MEGWVAWMNL GPR4_HUMAN 174 7 -
MEGWVAWMNL GPR4_PIG 174 7 -

Motif 5 width=13
Element Seqn Id St Int Rpt
VRGSVSTERQEKA GPR4_HUMAN 208 24 -
VRGSVSTERQEKA GPR4_PIG 208 24 -

Motif 6 width=16
Element Seqn Id St Int Rpt
SRSAIYLGRPWDCGFE GPR4_HUMAN 246 25 -
SRSAVYLGHPWDCGFE GPR4_PIG 246 25 -

Motif 7 width=19
Element Seqn Id St Int Rpt
ALHNLLRFLASDKPQEMAN GPR4_HUMAN 300 38 -
ALHNLLRFLTSDKPQEMAS GPR4_PIG 300 38 -

Motif 8 width=19
Element Seqn Id St Int Rpt
ASLTLETPLTSKRNSTAKA GPR4_HUMAN 319 0 -
ASLTLDTPLTSKRNSMARA GPR4_PIG 319 0 -
Final Motifs
Motif 1  width=22
Element Seqn Id St Int Rpt
MGNHTWEGCHVDSRVDHLFPPS GPR4_HUMAN 1 1 -
MGNGTWEGCHVDSRVDHLFPPS GPR4_PIG 1 1 -

Motif 2 width=13
Element Seqn Id St Int Rpt
RFARLRRVKTAVA GPR4_HUMAN 124 101 -
RFARLRRVKTAVA GPR4_PIG 124 101 -

Motif 3 width=19
Element Seqn Id St Int Rpt
ANSAPLFHDELFRDRYNHT GPR4_HUMAN 148 11 -
ANSVPLFHDELFRDRYNHT GPR4_PIG 148 11 -

Motif 4 width=10
Element Seqn Id St Int Rpt
MEGWVAWMNL GPR4_HUMAN 174 7 -
MEGWVAWMNL GPR4_PIG 174 7 -

Motif 5 width=13
Element Seqn Id St Int Rpt
VRGSVSTERQEKA GPR4_HUMAN 208 24 -
VRGSVSTERQEKA GPR4_PIG 208 24 -

Motif 6 width=16
Element Seqn Id St Int Rpt
SRSAIYLGRPWDCGFE GPR4_HUMAN 246 25 -
SRSAVYLGHPWDCGFE GPR4_PIG 246 25 -

Motif 7 width=19
Element Seqn Id St Int Rpt
ALHNLLRFLASDKPQEMAN GPR4_HUMAN 300 38 -
ALHNLLRFLTSDKPQEMAS GPR4_PIG 300 38 -

Motif 8 width=19
Element Seqn Id St Int Rpt
ASLTLETPLTSKRNSTAKA GPR4_HUMAN 319 0 -
ASLTLDTPLTSKRNSMARA GPR4_PIG 319 0 -