Abstract
alpha-Thrombin binding to and activation of platelets are of major importance in the initiation of physiologic thrombi and in the genesis of arterial thrombus formation. We have studied the site(s) and affinity of thrombin binding to human platelets. Our studies of the peptide inhibition of thrombin binding indicate that the glycoprotein Ib alpha binding site is of high affinity, Kd approximately 10(-10) M, while the seven-transmembrane-domain site is a moderate-affinity thrombin binding site, Kd approximately 10(-8) M. Further studies to modulate the high- or moderate-affinity thrombin binding can be directed to a specific class of sites. This would allow partial or total inhibition of specific thrombin-platelet interaction(s) in different clinical settings.
Full text
PDF




Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Brass L. F., Vassallo R. R., Jr, Belmonte E., Ahuja M., Cichowski K., Hoxie J. A. Structure and function of the human platelet thrombin receptor. Studies using monoclonal antibodies directed against a defined domain within the receptor N terminus. J Biol Chem. 1992 Jul 15;267(20):13795–13798. [PubMed] [Google Scholar]
- Cooper H. A., Bennett W. P., White G. C., 2nd, Wagner R. H. Hydrolysis of human platelet membrane glycoproteins with a Serratia marcescens metalloprotease: effect on response to thrombin and von Willebrand factor. Proc Natl Acad Sci U S A. 1982 Mar;79(5):1433–1437. doi: 10.1073/pnas.79.5.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Coughlin S. R., Vu T. K., Hung D. T., Wheaton V. I. Characterization of a functional thrombin receptor. Issues and opportunities. J Clin Invest. 1992 Feb;89(2):351–355. doi: 10.1172/JCI115592. [DOI] [PMC free article] [PubMed] [Google Scholar]
- De Marco L., Mazzucato M., Masotti A., Fenton J. W., 2nd, Ruggeri Z. M. Function of glycoprotein Ib alpha in platelet activation induced by alpha-thrombin. J Biol Chem. 1991 Dec 15;266(35):23776–23783. [PubMed] [Google Scholar]
- Fenton J. W., 2nd, Fasco M. J., Stackrow A. B. Human thrombins. Production, evaluation, and properties of alpha-thrombin. J Biol Chem. 1977 Jun 10;252(11):3587–3598. [PubMed] [Google Scholar]
- Fenton J. W., 2nd, Ofosu F. A., Moon D. G., Maraganore J. M. Thrombin structure and function: why thrombin is the primary target for antithrombotics. Blood Coagul Fibrinolysis. 1991 Feb;2(1):69–75. [PubMed] [Google Scholar]
- Ganguly P., Gould N. L. Thrombin receptors of human platelets: thrombin binding and antithrombin properties of glycoprotein I. Br J Haematol. 1979 May;42(1):137–145. doi: 10.1111/j.1365-2141.1979.tb03706.x. [DOI] [PubMed] [Google Scholar]
- Hortin G. L., Tollefsen D. M., Benutto B. M. Antithrombin activity of a peptide corresponding to residues 54-75 of heparin cofactor II. J Biol Chem. 1989 Aug 25;264(24):13979–13982. [PubMed] [Google Scholar]
- Hortin G. L., Trimpe B. L. Allosteric changes in thrombin's activity produced by peptides corresponding to segments of natural inhibitors and substrates. J Biol Chem. 1991 Apr 15;266(11):6866–6871. [PubMed] [Google Scholar]
- Hung D. T., Vu T. K., Wheaton V. I., Ishii K., Coughlin S. R. Cloned platelet thrombin receptor is necessary for thrombin-induced platelet activation. J Clin Invest. 1992 Apr;89(4):1350–1353. doi: 10.1172/JCI115721. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jamieson G. A., Okumura T. Reduced thrombin binding and aggregation in Bernard-Soulier platelets. J Clin Invest. 1978 Mar;61(3):861–864. doi: 10.1172/JCI109000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jandrot-Perrus M., Clemetson K. J., Huisse M. G., Guillin M. C. Thrombin interaction with platelet glycoprotein Ib: effect of glycocalicin on thrombin specificity. Blood. 1992 Dec 1;80(11):2781–2786. [PubMed] [Google Scholar]
- Jandrot-Perrus M., Huisse M. G., Krstenansky J. L., Bezeaud A., Guillin M. C. Effect of the hirudin carboxy-terminal peptide 54-65 on the interaction of thrombin with platelets. Thromb Haemost. 1991 Sep 2;66(3):300–305. [PubMed] [Google Scholar]
- Katagiri Y., Hayashi Y., Yamamoto K., Tanoue K., Kosaki G., Yamazaki H. Localization of von Willebrand factor and thrombin-interactive domains on human platelet glycoprotein Ib. Thromb Haemost. 1990 Feb 19;63(1):122–126. [PubMed] [Google Scholar]
- Larsen N. E., Simons E. R. Preparation and application of a photoreactive thrombin analogue: binding to human platelets. Biochemistry. 1981 Jul 7;20(14):4141–4147. doi: 10.1021/bi00517a030. [DOI] [PubMed] [Google Scholar]
- Liu L. W., Vu T. K., Esmon C. T., Coughlin S. R. The region of the thrombin receptor resembling hirudin binds to thrombin and alters enzyme specificity. J Biol Chem. 1991 Sep 15;266(26):16977–16980. [PubMed] [Google Scholar]
- Mazurov A. V., Vinogradov D. V., Vlasik T. N., Repin V. S., Booth W. J., Berndt M. C. Characterization of an antiglycoprotein Ib monoclonal antibody that specifically inhibits platelet-thrombin interaction. Thromb Res. 1991 Jun 15;62(6):673–684. doi: 10.1016/0049-3848(91)90371-3. [DOI] [PubMed] [Google Scholar]
- Munson P. J. LIGAND: a computerized analysis of ligand binding data. Methods Enzymol. 1983;92:543–576. doi: 10.1016/0076-6879(83)92044-x. [DOI] [PubMed] [Google Scholar]
- Nurden A. T., Caen J. P. Specific roles for platelet surface glycoproteins in platelet function. Nature. 1975 Jun 26;255(5511):720–722. doi: 10.1038/255720a0. [DOI] [PubMed] [Google Scholar]
- Okumura T., Hasitz M., Jamieson G. A. Platelet glycocalicin. Interaction with thrombin and role as thrombin receptor of the platelet surface. J Biol Chem. 1978 May 25;253(10):3435–3443. [PubMed] [Google Scholar]
- Scarborough R. M., Naughton M. A., Teng W., Hung D. T., Rose J., Vu T. K., Wheaton V. I., Turck C. W., Coughlin S. R. Tethered ligand agonist peptides. Structural requirements for thrombin receptor activation reveal mechanism of proteolytic unmasking of agonist function. J Biol Chem. 1992 Jul 5;267(19):13146–13149. [PubMed] [Google Scholar]
- Takamatsu J., Horne M. K., 3rd, Gralnick H. R. Identification of the thrombin receptor on human platelets by chemical crosslinking. J Clin Invest. 1986 Feb;77(2):362–368. doi: 10.1172/JCI112313. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Van Deerlin V. M., Tollefsen D. M. The N-terminal acidic domain of heparin cofactor II mediates the inhibition of alpha-thrombin in the presence of glycosaminoglycans. J Biol Chem. 1991 Oct 25;266(30):20223–20231. [PubMed] [Google Scholar]
- Vassallo R. R., Jr, Kieber-Emmons T., Cichowski K., Brass L. F. Structure-function relationships in the activation of platelet thrombin receptors by receptor-derived peptides. J Biol Chem. 1992 Mar 25;267(9):6081–6085. [PubMed] [Google Scholar]
- Vu T. K., Hung D. T., Wheaton V. I., Coughlin S. R. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell. 1991 Mar 22;64(6):1057–1068. doi: 10.1016/0092-8674(91)90261-v. [DOI] [PubMed] [Google Scholar]
- Vu T. K., Wheaton V. I., Hung D. T., Charo I., Coughlin S. R. Domains specifying thrombin-receptor interaction. Nature. 1991 Oct 17;353(6345):674–677. doi: 10.1038/353674a0. [DOI] [PubMed] [Google Scholar]
- Wicki A. N., Clemetson K. J. Structure and function of platelet membrane glycoproteins Ib and V. Effects of leukocyte elastase and other proteases on platelets response to von Willebrand factor and thrombin. Eur J Biochem. 1985 Nov 15;153(1):1–11. doi: 10.1111/j.1432-1033.1985.tb09259.x. [DOI] [PubMed] [Google Scholar]
- Witting J. I., Bourdon P., Brezniak D. V., Maraganore J. M., Fenton J. W., 2nd Thrombin-specific inhibition by and slow cleavage of hirulog-1. Biochem J. 1992 May 1;283(Pt 3):737–743. doi: 10.1042/bj2830737. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Witting J. I., Bourdon P., Maraganore J. M., Fenton J. W., 2nd Hirulog-1 and -B2 thrombin specificity. Biochem J. 1992 Oct 15;287(Pt 2):663–664. doi: 10.1042/bj2870663. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yamamoto N., Greco N. J., Barnard M. R., Tanoue K., Yamazaki H., Jamieson G. A., Michelson A. D. Glycoprotein Ib (GPIb)-dependent and GPIb-independent pathways of thrombin-induced platelet activation. Blood. 1991 Apr 15;77(8):1740–1748. [PubMed] [Google Scholar]