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.
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).
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 . 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 . 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 . 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 .
S1P is released from activated platelets and is also produced by a number
of other cell types in response to growth factors and cytokines . 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 . 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 . 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.
S1PRECEPTOR is a 7-element fingerprint that provides a signature for the
sphingosine 1-phosphate receptor family. The fingerprint was derived from an
initial alignment of 10 sequences: the motifs were drawn from conserved
regions spanning virtually the full alignment length, focusing on those
areas of the alignment that characterise the sphingosine 1-phosphate
receptors but distinguish them from the rest of the rhodopsin-like
superfamily - motif 1 resides at the N-terminus; motif 2 lies at the
C-terminus of TM domain 2, leading into the first external loop; motif 3 is
located in the first external loop, leading into TM domain 3; motif 4
resides in the N-terminal portion of TM domain 5; motif 5 spans part of TM
domain 5, leading into the third cytoplasmic loop; motif 6 spans the third
external loop; and motif 7 lies at the C-terminus of TM domain 7. Two
iterations on SPTR39_15f were required to reach convergence, at which point
a true set comprising 15 sequences was identified. A single partial match
was also found, CB1A_FUGRU, a member of the closely related cannabinoid
receptor family that matches motifs 5 and 7.