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| THE REGION OF THE THROMBIN RECEPTOR RESEMBLING HIRUDIN BINDS TO THROMBIN AND ALTERS ENZYME SPECIFICITY |
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| Author(s): LIU LW, VU TKH, ESMON CT, COUGHLIN SR |
| Source: JOURNAL OF BIOLOGICAL CHEMISTRY Volume: 266 Issue: 26 Pages: 16977-16980 Published: SEP 15 1991 |
| Times Cited: 194 References: 17 |
| Abstract: 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 (K(i) = 0.96 mM and 0.6-mu-M, 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 (K(d) = 32 +/- 7-mu-M). 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. |
| Document Type: Note |
| Language: English |
Addresses:
1. OKLAHOMA MED RES FDN, HOWARD HUGHES MED INST, 820 NE 15 ST, OKLAHOMA CITY, OK 73104 USA
2. UNIV OKLAHOMA, HLTH SCI CTR, DEPT BIOCHEM, OKLAHOMA CITY, OK 73190 USA
3. UNIV OKLAHOMA, HLTH SCI CTR, DEPT PATHOL, OKLAHOMA CITY, OK 73190 USA
4. OKLAHOMA MED RES FDN, CARDIOVASC BIOL RES PROGRAM, OKLAHOMA CITY, OK 73104 USA
5. UNIV CALIF SAN FRANCISCO, DEPT MED, SAN FRANCISCO, CA 94143 USA
6. UNIV CALIF SAN FRANCISCO, CARDIOVASC RES INST, SAN FRANCISCO, CA 94143 USA |
| Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 |
| Subject Category: Biochemistry & Molecular Biology |
| IDS Number: GF445 |
| ISSN: 0021-9258 |
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| | | | | | | | | Record from Web of Science® | | | | | | | | | |