SPECIFICITY OF THE THROMBIN RECEPTOR FOR AGONIST PEPTIDE IS DEFINED BY ITS EXTRACELLULAR SURFACE

G-PROTEIN-COUPLED receptors for catecholamines and some other small li gands are activated when agonists bind to the transmembrane region of the receptor1. The docking interactions through which peptide agonists activate their receptors are less well characterized2-7. The thrombin receptor is a specialized peptide receptor. it is activated by bindin g its tethered ligand domain, which is unmasked upon receptor cleavage by thrombin8,9. Human and Xenopus thrombin receptor homologues are ea ch selectively activated by the agonist peptide representing their res pective tethered ligand domains. Here we identify receptor domains tha t confer this agonist specificity by replacing the Xenopus receptor's amino-terminal exodomain and three extracellular loops with the corres ponding human structures. This switches receptor specificity from Xeno pus to human. The specificity of these thrombin receptors for their re spective peptide agonists is thus determined by their extracellular su rfaces. Our results indicate that agonist interaction with extracellul ar domains is important for thrombin receptor activation.