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Tethered ligand agonist peptides. Structural requirements for thrombin receptor activation reveal mechanism of proteolytic unmasking of agonist function

The Journal of biological chemistry, 1992-07, Vol.267 (19), p.13146-13149 [Peer Reviewed Journal]

1993 INIST-CNRS ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1016/s0021-9258(18)42184-9 ;PMID: 1320011 ;CODEN: JBCHA3

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Title:
Tethered ligand agonist peptides. Structural requirements for thrombin receptor activation reveal mechanism of proteolytic unmasking of agonist function
Author: SCARBOROUGH, R. M ; NAUGHTON, M. A ; TENG, W ; HUNG, D. T ; ROSE, J ; VU, T.-K. H ; WHEATON, V. I ; TURCK, C. W ; COUGHLIN, S. R
Subjects: Amino Acid Sequence ; Analytical, structural and metabolic biochemistry ; Animals ; binding ; Biological and medical sciences ; Cell Line ; Fundamental and applied biological sciences. Psychology ; Humans ; Hydrolysis ; man ; Molecular Sequence Data ; Mutagenesis ; Peptides - metabolism ; Phosphatidylinositols - metabolism ; platelets ; Proteins ; Rats ; receptors ; Receptors, Cell Surface - genetics ; Receptors, Cell Surface - metabolism ; Receptors, Thrombin ; Structure-Activity Relationship ; structure-activity relationships ; thrombin ; Thrombin - metabolism ; Xenopus
Is Part Of: The Journal of biological chemistry, 1992-07, Vol.267 (19), p.13146-13149
Description: The human platelet thrombin receptor is activated when thrombin cleaves its receptor's amino-terminal extension to reveal a new amino terminus that functions as a tethered peptide ligand. Exactly how this "agonist peptide domain" remains cryptic within the uncleaved receptor and becomes functional after receptor cleavage is unknown. In this report we define the structural features of the thrombin receptor's agonist peptide domain important for receptor activation. Studies with mutant thrombin receptors have suggested that agonist peptide domain residues 2-6 contained determinants critical for receptor activation, and the synthetic peptide SFLLR-NH2 representing the 1st 5 amino-terminal residues of the agonist peptide domain was sufficient to specify agonist activity. Acetylating or removing the agonist peptide's amino-terminal ammonium group greatly attenuated agonist activity. Agonist peptide residue Phe2 was vital for agonist function; residues Leu4 and Arg5 individually played less important roles. These structure-function relationships held for both platelet activation and activation of the cloned receptor expressed in transfected mammalian cells. Our studies suggest that structures at the extreme amino terminus of the thrombin receptor's agonist peptide domain, in particular the free ammonium group of Ser1 and the phenyl ring of Phe2, are critical for receptor activation and that the agonist function of this domain is expressed when receptor proteolysis unmasks such determinants. In addition to revealing details of the thrombin receptor's proteolytic triggering mechanism, these studies open avenues to the development of drugs targeting the thrombin receptor and to further definition for the role of the thrombin receptor in cellular regulation.
Publisher: Bethesda, MD: American Society for Biochemistry and Molecular Biology
Language: English
Identifier: ISSN: 0021-9258
EISSN: 1083-351X
DOI: 10.1016/s0021-9258(18)42184-9
PMID: 1320011
CODEN: JBCHA3
Source: MEDLINE
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Tethered ligand agonist peptides. Structural requirements for thrombin receptor activation reveal mechanism of proteolytic unmasking of agonist function

1993 INIST-CNRS ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1016/s0021-9258(18)42184-9 ;PMID: 1320011 ;CODEN: JBCHA3

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