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PR01569

Identifier
P2Y12PRNCPTR  [View Relations]  [View Alignment]  
Accession
PR01569
No. of Motifs
3
Creation Date
08-AUG-2001  (UPDATE 10-DEC-2001)
Title
P2Y12 purinoceptor signature
Database References
PRINTS; PR90007 7TM; PR90006 GPCRCLAN; PR00237 GPCRRHODOPSN
PRINTS; PR01157 P2YPURNOCPTR
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. WATSON, S. AND ARKINSTALL, S.
Adenosine and adenine nucleotides.
IN THE G PROTEIN-LINKED RECEPTOR FACTSBOOK, ACADEMIC PRESS, 1994, PP.19-31.
 
7. COMMUNI, D., JANSSENS, R., SUAREZ-HUERTA, N., ROBAYE, B. AND BOEYNAEMS, J.
Advances in signalling by extracellular nucleotides: the role and 
transduction mechanisms of P2Y receptors.
CELL SIGNAL. 12 351-360 (2000).
 
8. ZHANG, F., LUO, L., GUSTAFSON, E., LACHOWICZ, J., SMITH, M., QIAO, X., 
LIU, Y., CHEN, G., PRAMANIK, B., LAZ, T., PALMER, K., BAYNE, M. AND 
MONSMA, F.
ADP is the cognate ligand for the orphan G protein-coupled receptor SP1999.
J.BIOL.CHEM. 2001 276 8608-8615 (2001).
 
9. HOLLOPETER, G., JANTZEN, H.M., VINCENT D., LI, G., ENGLAND, L., 
RAMAKRISHNAN, V., YANG, R.B., NURDEN, P., NURDEN, A., JULIUS, D. AND
CONLEY, P.B.
Identification of the platelet ADP receptor targeted by antithrombotic drugs.
NATURE 409 202-207 (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 [1,2]. 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].
 
In addition to their roles in energy metabolism, extracellular nucleotides 
(such as ATP) can act as signalling molecules to induce a wide variety of 
biological effects. They are released into the extracellular fluid as a 
result of cell lysis, exocytosis of nucleotide-containing granules or by 
efflux through membrane transport proteins, and can function as autocrine 
and paracrine mediators [6,7]. Nucleotides play a role in synaptic 
transmission and in platelet-vessel wall interactions. In neurons of the 
central and peripheral nervous system, ATP is colocalised and cosecreted 
with more traditional neurotransmitters, such as catecholamines and 
acetylcholine, and has excitatory effects [6,7]. ATP is also found in high 
concentrations in the dense granules of platelets, together with ADP. These 
granules also contain lower levels of other nucleotides, such as adenine 
dinucleotides, GTP and UTP [7]. In addition, ADP is released from the 
vascular endothelium following injury and causes activation of platelets [6].
 
Receptors for adenine nucleotides are collectively termed P2 purinoceptors. 
They can be further subdivided into two structural classes: P2X receptors 
are ligand-gated ion channels, while P2Y receptors are G protein-coupled 
receptors. P2Y receptors have also been identified that are selective for 
uridine (rather than adenine) nucleotides [7]. 
 
cDNA encoding a platelet ADP receptor, designated P2Y12, has been isolated 
and functionally characterised [8,9]. The receptor is coupled to the 
inhibition of adenylyl cyclase through Gi. In conjunction with P2Y1, P2Y12 
receptors mediate ADP-induced platelet aggregation [8,9]. The receptor is a 
target of the thienopyridine antithrombotic drugs clopidogrel and
ticlopidine, which have been demonstrated to be effective in treating a 
variety of thrombotic diseases [9].
 
P2Y12PRNCPTR is a 3-element fingerprint that provides a signature for the
P2Y12 purinoceptor. The fingerprint was derived from an initial alignment 
of 2 sequences: the motifs were drawn from conserved regions spanning the 
C-terminal two thirds of the alignment, focusing on those sections that 
characterise the P2Y12 receptors but distinguish them from the rest of the 
P2Y receptor family - motif 1 spans part of the second intracellular loop
and part of TM domain 4; motif 2 spans part of the third intracellular loop,
leading into TM domain 6; and motif 3 resides within the cytoplasmic 
C-terminal region. Two iterations on SPTR39.22_17.3f were required to reach
convergence, at which point a true set comprising 4 sequences was identified. 
Summary Information
4 codes involving  3 elements
0 codes involving 2 elements
Composite Feature Index
3444
2000
123
True Positives
Q9BGT8        Q9CPV9        Q9EPX4        Q9H244        
Sequence Titles
Q9BGT8      HYPOTHETICAL 39.5 KDA PROTEIN - Macaca fascicularis (Crab eating macaque) (Cynomolgus monkey). 
Q9CPV9 4921504D23RIK PROTEIN (2900079B22RIK PROTEIN) - Mus musculus (Mouse).
Q9EPX4 P2Y12 PLATELET ADP RECEPTOR - Rattus norvegicus (Rat).
Q9H244 P2Y12 PLATELET ADP RECEPTOR (G-PROTEIN COUPLED RECEPTOR SP1999) - Homo sapiens (Human).
Scan History
SPTR39.22_17.3f 2  200  NSINGLE    
Initial Motifs
Motif 1  width=16
Element Seqn Id St Int Rpt
SSPSNLLGAKILSVAI Q9EPX4 139 139 -
SNPKNLLGAKILSVVI Q9H244 133 133 -

Motif 2 width=29
Element Seqn Id St Int Rpt
RSYVRTRGSAKAPKKRVNIKVFIIIAVFF Q9EPX4 224 69 -
RSYVRTRGVGKVPRKKVNVKVFIIIAVFF Q9H244 218 69 -

Motif 3 width=20
Element Seqn Id St Int Rpt
FRNSLMSMLRCSTSGANKKK Q9EPX4 311 58 -
FRNSLISMLKCPNSATSLSQ Q9H244 305 58 -
Final Motifs
Motif 1  width=16
Element Seqn Id St Int Rpt
SSPSNLLGAKILSVAI Q9EPX4 139 139 -
SNPKNLLGAKILSVVI Q9H244 133 133 -
SNPKNLLGAKILSVLI Q9BGT8 133 133 -
SSPSNLLGAKILSVVI Q9CPV9 139 139 -

Motif 2 width=29
Element Seqn Id St Int Rpt
RSYVRTRGSAKAPKKRVNIKVFIIIAVFF Q9EPX4 224 69 -
RSYVRTRGVGKVPRKKVNVKVFIIIAVFF Q9H244 218 69 -
RSYVRTRGVGKVPRKKVNVKVFIIIAVFF Q9BGT8 218 69 -
RSYVRTRGSAKVPKKKVNVKVFIIIAVFF Q9CPV9 224 69 -

Motif 3 width=20
Element Seqn Id St Int Rpt
FRNSLMSMLRCSTSGANKKK Q9EPX4 311 58 -
FRNSLISMLKCPNSATSLSQ Q9H244 305 58 -
FRNSLISMLKCPNSATSQSQ Q9BGT8 305 58 -
FRNSLTSMLRCSNSTSTSGT Q9CPV9 311 58 -