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PR01563

Identifier
G2ARECEPTOR  [View Relations]  [View Alignment]  
Accession
PR01563
No. of Motifs
8
Creation Date
17-AUG-2001
Title
G2A 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. 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).
 
9. LE, L.Q., KABAROWSKI, J.H., WENG, Z., SATTERTHWAITE, A.B., HARVILL, E.T.,
JENSEN, E.R., MILLER, J.F. AND WITTE, O.N.
Mice lacking the orphan G protein-coupled receptor G2A develop a late-onset
autoimmune syndrome.
IMMUNITY 14(5) 561-571 (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]. 
 
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 [8].
 
An orphan receptor, G2A, has recently been identified that acts as a high 
affinity receptor for LPC and a lower affinity receptor for the related
lysophospholipid, SPC [8]. G2A is expressed mainly in lymphocytes and its
expression is up-regulated by stress and prolonged mitogenic signals. Mice
lacking the receptor have been found to develop a late-onset autoimmune
disease [9]. It has therefore been suggested that G2A may function as a
sensor of LPC levels at sites of inflammation and act as a negative
regulator of lymphocyte growth to limit expansion of tissue-infiltrating
cells and overt autoimmune disease [8]. Activation of G2A by LPC results in
an increase in intracellular calcium levels (through coupling to Gi
proteins) and activation of MAP kinases. The receptor has also been shown 
to couple to G13 proteins, causing RhoA activation and formation of actin
stress fibers [9].
 
G2ARECEPTOR is an 8-element fingerprint that provides a signature for the
G2A lysophosphatidylcholine receptors. The fingerprint was derived from an
initial alignment of 3 sequences: the motifs were drawn from conserved
regions spanning virtually the full alignment length, focusing on those
sections that characterise the G2A receptors but distinguish them from the 
rest of the lysophospholipid receptor family - motif 1 lies in the first 
external loop; motif 2 spans the second cytoplasmic loop; motif 3 resides 
in TM domain 4; motif 4 lies in the second external loop, leading into TM 
domain 5; motif 5 encodes the C-terminal portion of TM domain 5, leading 
into the third cytoplasmic loop; motif 6 is located in the third external 
loop; motif 7 spans part of TM domain 7, leading into the C-terminus; and 
motif 8 also resides 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. A single partial match was found,
Q9BSU2, a human G2A receptor fragment that fails to match motifs 1-3.
Summary Information
   2 codes involving  8 elements
0 codes involving 7 elements
0 codes involving 6 elements
1 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
500011111
400000000
300000000
200000000
12345678
True Positives
Q9UNW8        Q9Z282        
True Positive Partials
Codes involving 5 elements
Q9BSU2
Sequence Titles
Q9UNW8      G PROTEIN-COUPLED RECEPTOR - Homo sapiens (Human). 
Q9Z282 G PROTEIN-COUPLED RECEPTOR G2A - Mus musculus (Mouse).

Q9BSU2 G PROTEIN-COUPLED RECEPTOR - Homo sapiens (Human).
Scan History
SPTR39.22_17.3f 1  90   NSINGLE    
Initial Motifs
Motif 1  width=11
Element Seqn Id St Int Rpt
IYIRNQHRWTL Q9UNW8 100 100 -
IYIQNQHKWNL Q9Z282 97 97 -

Motif 2 width=13
Element Seqn Id St Int Rpt
VYALESRGRRRRR Q9UNW8 145 34 -
VYALESRGHRHQR Q9Z282 142 34 -

Motif 3 width=11
Element Seqn Id St Int Rpt
CIFILVGIVHY Q9UNW8 165 7 -
CVILLVGLVNY Q9Z282 162 7 -

Motif 4 width=10
Element Seqn Id St Int Rpt
DSRIAGYYYA Q9UNW8 193 17 -
NSKIAGYHYL Q9Z282 191 18 -

Motif 5 width=12
Element Seqn Id St Int Rpt
AFTNHRIFRSIK Q9UNW8 216 13 -
AFTNHQIFRSIK Q9Z282 214 13 -

Motif 6 width=11
Element Seqn Id St Int Rpt
KAAAFSYYRGD Q9UNW8 265 37 -
KAASFSFYQGD Q9Z282 263 37 -

Motif 7 width=22
Element Seqn Id St Int Rpt
TDHSRQEVSRIHKGWKEWSMKT Q9UNW8 312 36 -
TDHSRQEVSRIHTGWKKWSTKT Q9Z282 310 36 -

Motif 8 width=12
Element Seqn Id St Int Rpt
YTFSRPVHPPGS Q9UNW8 357 23 -
YTFPNPAHPPGS Q9Z282 352 20 -
Final Motifs
Motif 1  width=11
Element Seqn Id St Int Rpt
IYIRNQHRWTL Q9UNW8 100 100 -
IYIQNQHKWNL Q9Z282 97 97 -

Motif 2 width=13
Element Seqn Id St Int Rpt
VYALESRGRRRRR Q9UNW8 145 34 -
VYALESRGHRHQR Q9Z282 142 34 -

Motif 3 width=11
Element Seqn Id St Int Rpt
CIFILVGIVHY Q9UNW8 165 7 -
CVILLVGLVNY Q9Z282 162 7 -

Motif 4 width=10
Element Seqn Id St Int Rpt
DSRIAGYYYA Q9UNW8 193 17 -
NSKIAGYHYL Q9Z282 191 18 -

Motif 5 width=12
Element Seqn Id St Int Rpt
AFTNHRIFRSIK Q9UNW8 216 13 -
AFTNHQIFRSIK Q9Z282 214 13 -

Motif 6 width=11
Element Seqn Id St Int Rpt
KAAAFSYYRGD Q9UNW8 265 37 -
KAASFSFYQGD Q9Z282 263 37 -

Motif 7 width=22
Element Seqn Id St Int Rpt
TDHSRQEVSRIHKGWKEWSMKT Q9UNW8 312 36 -
TDHSRQEVSRIHTGWKKWSTKT Q9Z282 310 36 -

Motif 8 width=12
Element Seqn Id St Int Rpt
YTFSRPVHPPGS Q9UNW8 357 23 -
YTFPNPAHPPGS Q9Z282 352 20 -