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Identification of a novel thrombin receptor sequence required for
activation-dependent responses
WF Bahou, JL Kutok, A Wong, CL Potter and BS Coller
Department of Medicine, State University of New York at Stony Brook.
Thrombin receptor (TR) activation by alpha-thrombin requires proteolytic
cleavage, although synthetic peptides modeled after the new N-terminus
directly effect receptor activation without cleavage, presumably by
interacting with an unidentified region of the receptor. To further define
critical residues responsible for receptor activation, we performed epitope
mapping of anti-TR1-160, a previously described polyclonal antibody that
inhibits peptide ligand-induced receptor activation in various cell types
expressing a functional TR. An enzyme-linked immunosorbent assay (ELISA)
using overlapping decapeptides derived from the TR extracellular domains
identified four immunodominant peaks within the long N-terminal extension
centered between amino acids 34-44, 48-67, 65-79, and 87-94. Soluble
peptides derived from regions 83-94, but not those from other regions of
the receptor, neutralized the ability of anti-TR1-160 to inhibit peptide
ligand-induced platelet aggregation, suggesting that antibodies directed
against this region of the TR are important in ligand-mediated activation.
Thrombin receptor mutants lacking discrete regions of the TR were
subsequently evaluated using microinjected Xenopus oocytes. Whereas a TR
mutant lacking amino acid residues Thr67-Lys82 (TR delta 67-82) showed
normal to exaggerated responses to either alpha-thrombin or synthetic
peptide ligands, only TR mutants with limited deletions spanning the
residues Gln83-Ser93 exhibited dysfunctional responses to either agonist
(200 nmol/L alpha-thrombin or 200 mumol/L TR42-47). These data provide a
model for receptor activation that implicates a discrete and previously
uncharacterized sequence within the TR N- terminal extension that is
necessary for initiation of signal transduction events independent of the
initiating agonist.
Volume 84,
Issue 12,
pp. 4195-4202,
12/15/1994
Copyright © 1994 by The American Society of Hematology
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