| 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. ISHIHARA, H., CONNOLLY, A.J., ZENG, D., KAHN, M.L., ZHENG, Y.W.,
TIMMONS, C., TRAM T. AND COUGHLIN, S.R.
Protease-activated receptor 3 is a second thrombin receptor in humans
NATURE 386 502-506 (1997).
7.NYSTEDT, S., LARSSON, A.K., ABERG, H. AND SUNDELIN, J.
The mouse proteinase-activated receptor-2 cDNA and gene. Molecular cloning
and functional expression.
J.BIOL.CHEM. 270 5950-5955 (1995).
8. KAHN, M., ISHII, K., KUO, W.L., PIPER, M., CONNOLLY, A., SHI, Y.P.,
WU, R., LIN, C.C. AND COUGHLIN, S.R.
Conserved structure and adjacent location of the thrombin receptor and
protease-activated receptor 2 genes define a protease-activated receptor
gene cluster
MOL.MED. 2 349-357 (1996).
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| 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].
Thrombin is a coagulation protease that activates platelets, leukocytes,
endothelial and mesenchymal cells at sites of vascular injury, acting partly
through an unusual proteolytically activated GPCR [6]. Gene knockout
experiments have provided definitive evidence for a second thrombin receptor
in mouse platelets and have suggested tissue-specific roles for different
thrombin receptors. Because the physiological agonist at the receptor was
originally unknown, it was provisionally named protease-activated receptor
(PAR) [7]. At least 4 PAR subtypes have now been characterised. Thus, the
thrombin and PAR receptors constitute a fledgling receptor family that
shares a novel proteolytic activation mechanism [8].
PROTEASEAR is a 5-element fingerprint that provides a signature for
protease activated receptors. The fingerprint was derived from an initial
alignment of 7 sequences: the motifs were drawn from short conserved regions
spanning the full alignment length, focusing on those sections that
characterise the protease activated receptors but distinguish them from
the rest of the rhodopsin-like superfamily - motif 1 spans the N-terminal
portion of TM domain 1; motif 2 lies within the first extracellular loop;
motifs 3 and 4 encode the N-terminal portions of TM domains 5 and 6
respectively; and motif 5 spans the third external loop. A single iteration
on SPTR37_10f was required to reach convergence, no further sequences being
identified beyond the starting set. Three partial matches were found:
GPRH_HUMAN and O95853 are putative GPCR from Homo sapiens that match motifs
2 and 4; and THRR_PAPHA is thrombin receptor precursor from Papio hamadryas
that matches motifs 1 and 2.
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