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The region of the thrombin receptor resembling hirudin binds to thrombin and alters enzyme specificity

The Journal of biological chemistry, 1991-09, Vol.266 (26), p.16977-16980 [Peer Reviewed Journal]

1992 INIST-CNRS ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1016/S0021-9258(19)47326-2 ;PMID: 1654318 ;CODEN: JBCHA3

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Title:
The region of the thrombin receptor resembling hirudin binds to thrombin and alters enzyme specificity
Author: LE-WEN LIU ; VU, T.-K. H ; ESMOND, C. T ; COUGHLIN, S. R
Subjects: Amino Acid Sequence ; Analytical, structural and metabolic biochemistry ; Binding Sites ; Binding, Competitive ; Biological and medical sciences ; Enzymes and enzyme inhibitors ; Fundamental and applied biological sciences. Psychology ; hirudin ; Hirudins - chemistry ; Hirudins - metabolism ; Humans ; Hydrolases ; Molecular Sequence Data ; Protein Conformation ; Receptors, Cell Surface - chemistry ; Receptors, Cell Surface - metabolism ; Receptors, Thrombin ; Substrate Specificity ; Thrombin - metabolism
Is Part Of: The Journal of biological chemistry, 1991-09, Vol.266 (26), p.16977-16980
Description: A thrombin receptor has recently been cloned and the sequence deduced. The sequence reveals a thrombin cleavage site that accounts for receptor activation. The receptor also has an acidic region with some similarities to the carboxyl-terminal region of the leech thrombin inhibitor, hirudin. Synthetic peptides corresponding to the receptor cleavage site (residues 38-45), the hirudin-like domain (residues 52-69), and the covalently associated domains (residues 38-64) were evaluated for their ability to bind to thrombin. Peptides 38-45 and 38-64 were competitive inhibitors of thrombin's chromogenic substrate activity (Ki = 0.96 mM and 0.6 microM, respectively. Residues 52-69 altered the chromogenic substrate specificity, resulting in accelerated cleavage of some substrates and inhibited cleavage of others. The same peptide binds to thrombin and alters the fluorescence emission intensity of 5-dimethylaminonaphthalene-1-sulfonyl (dansyl)-thrombin in which the dansyl is attached directly to the active site serine (Kd = 32 +/- 7 microM). Residues 52-69 displace the carboxyl-terminal peptide of hirudin, indicating that they share a common binding site in the anion exosite of thrombin. These data suggest that the thrombin receptor has high affinity for thrombin due to the presence of the hirudin-like domain and that this domain alters the specificity of thrombin. This change in specificity may account for the ability of the receptor to serve as an excellent thrombin substrate despite the presence of an Asp residue in the P3 site, which is normally inhibitory to thrombin activity.
Publisher: Bethesda, MD: American Society for Biochemistry and Molecular Biology
Language: English
Identifier: ISSN: 0021-9258
EISSN: 1083-351X
DOI: 10.1016/S0021-9258(19)47326-2
PMID: 1654318
CODEN: JBCHA3
Source: MEDLINE
Alma/SFX Local Collection

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The region of the thrombin receptor resembling hirudin binds to thrombin and alters enzyme specificity

1992 INIST-CNRS ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1016/S0021-9258(19)47326-2 ;PMID: 1654318 ;CODEN: JBCHA3

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