Paul E. Bock, Ph.D.

Professor

paul.bock@vanderbilt.edu
Faculty Appointments
Professor of Pathology, Microbiology and Immunology Professor of Medicine
Education
Ph.D., Biochemistry, Washington University, Saint Louis, MissouriB.A., Biology, University of California, San Diego, California
Office Address
C3321A Medical Center North
TN 37232-2561
Research Description
Research in this laboratory is focused on molecular mechanisms of human blood coagulation and fibrinolysis and their roles in cardiovascular and infectious diseases. Biochemical and biophysical techniques are being used to determine how the proteolytic enzymes of blood coagulation and fibrinolysis are regulated through interactions with specific physiological and pathological proteins, and the membrane surfaces of vascular cells. Present work focuses on three areas: (1) The mechanism by which coagulation factor Va regulates the formation of the active blood clotting proteinase, thrombin, from its inactive precursor, prothrombin, and the mechanisms of thrombin regulation; (2) The mechanism of non-proteolytic activation of prothrombin by the Streptococcus aureus protein, staphylocoagulase and its homologs, and their roles in the molecular pathology of infections of heart valves in acute bacterial endocarditis; and (3) The mechanism of activation of plasminogen by the streptococcal protein, streptokinase, which is the basis for its critical role as a virulence factor in life-threatening streptococcal infections. Fluorescence spectroscopy, protein chemistry, enzyme kinetics, and molecular biology approaches are being used to define the roles of protein conformational changes and the assembly of macromolecular complexes in these mechanisms. The goal of the research is to develop molecular descriptions of these systems, which are necessary for development of new therapeutic approaches for treatment of thrombosis, and for inhibitory targeting of bacterial pathogenicity factors that usurp the human coagulation and fibrinolytic systems to propagate infectious diseases.
Research Keywords
Blood coagulation, Fibrinolysis, Enzyme mechanisms, Protein structure, Biochemistry, Biophysics, Fluorescence spectroscopy, Bacterial virulence factors, Pathology, Infectious diseases, Cardiovascular diseases
Publications
Laha M, Panizzi P, Nahrendorf M, Bock PE. Engineering streptokinase for generation of active site-labeled plasminogen analogs. Anal. Biochem [print-electronic]. 2011 Aug 8/15/2011; 415(2): 105-15. PMID: 21570944, PMCID: PMC3114107, PII: S0003-2697(11)00265-X, DOI: 10.1016/j.ab.2011.04.025, ISSN: 1096-0309.

Kroh HK, Panizzi P, Tchaikovski S, Baird TR, Wei N, Krishnaswamy S, Tans G, Rosing J, Furie B, Furie BC, Bock PE. Active site-labeled prothrombin inhibits prothrombinase in vitro and thrombosis in vivo. J. Biol. Chem [print-electronic]. 2011 Jul 7/1/2011; 286(26): 23345-56. PMID: 21531712, PMCID: PMC3123099, PII: M111.230292, DOI: 10.1074/jbc.M111.230292, ISSN: 1083-351X.

Wiles KG, Panizzi P, Kroh HK, Bock PE. Skizzle is a novel plasminogen- and plasmin-binding protein from Streptococcus agalactiae that targets proteins of human fibrinolysis to promote plasmin generation. J. Biol. Chem [print-electronic]. 2010 Jul 7/2/2010; 285(27): 21153-64. PMID: 20435890, PMCID: PMC2898333, PII: M110.107730, DOI: 10.1074/jbc.M110.107730, ISSN: 1083-351X.

Tharp AC, Laha M, Panizzi P, Thompson MW, Fuentes-Prior P, Bock PE. Plasminogen substrate recognition by the streptokinase-plasminogen catalytic complex is facilitated by Arg253, Lys256, and Lys257 in the streptokinase beta-domain and kringle 5 of the substrate. J. Biol. Chem [print-electronic]. 2009 Jul 7/17/2009; 284(29): 19511-21. PMID: 19473980, PMCID: PMC2740577, PII: M109.005512, DOI: 10.1074/jbc.M109.005512, ISSN: 0021-9258.

Kroh HK, Panizzi P, Bock PE. Von Willebrand factor-binding protein is a hysteretic conformational activator of prothrombin. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2009 May 5/12/2009; 106(19): 7786-91. PMID: 19416890, PMCID: PMC2683071, PII: 0811750106, DOI: 10.1073/pnas.0811750106, ISSN: 1091-6490.

Verhamme IM, Bock PE. Rapid-reaction kinetic characterization of the pathway of streptokinase-plasmin catalytic complex formation. J. Biol. Chem [print-electronic]. 2008 Sep 9/19/2008; 283(38): 26137-47. PMID: 18658146, PMCID: PMC2533780, PII: M804038200, DOI: 10.1074/jbc.M804038200, ISSN: 0021-9258.

Smith SB, Verhamme IM, Sun MF, Bock PE, Gailani D. Characterization of Novel Forms of Coagulation Factor XIa: independence of factor XIa subunits in factor IX activation. J. Biol. Chem [print-electronic]. 2008 Mar 3/14/2008; 283(11): 6696-705. PMID: 18192270, PMCID: PMC2633474, PII: M707234200, DOI: 10.1074/jbc.M707234200, ISSN: 0021-9258.

Hacisalihoglu A, Panizzi P, Bock PE, Camire RM, Krishnaswamy S. Restricted active site docking by enzyme-bound substrate enforces the ordered cleavage of prothrombin by prothrombinase. J. Biol. Chem [print-electronic]. 2007 Nov 11/9/2007; 282(45): 32974-82. PMID: 17848548, PMCID: PMC2292459, PII: M706529200, DOI: 10.1074/jbc.M706529200, ISSN: 0021-9258.

Munnix IC, Kuijpers MJ, Auger J, Thomassen CM, Panizzi P, van Zandvoort MA, Rosing J, Bock PE, Watson SP, Heemskerk JW. Segregation of platelet aggregatory and procoagulant microdomains in thrombus formation: regulation by transient integrin activation. Arterioscler. Thromb. Vasc. Biol [print-electronic]. 2007 Nov; 27(11): 2484-90. PMID: 17761939, PMCID: PMC2376762, PII: ATVBAHA.107.151100, DOI: 10.1161/ATVBAHA.107.151100, ISSN: 1524-4636.

Bock PE, Panizzi P, Verhamme IM. Exosites in the substrate specificity of blood coagulation reactions. J. Thromb. Haemost. 2007 Jul; 5 Suppl 1: 81-94. PMID: 17635714, PMCID: PMC2291348, PII: JTH2496, DOI: 10.1111/j.1538-7836.2007.02496.x, ISSN: 1538-7933.

Kroh HK, Tans G, Nicolaes GA, Rosing J, Bock PE. Expression of allosteric linkage between the sodium ion binding site and exosite I of thrombin during prothrombin activation. J. Biol. Chem [print-electronic]. 2007 Jun 6/1/2007; 282(22): 16095-104. PMID: 17430903, PMCID: PMC2292469, PII: M610577200, DOI: 10.1074/jbc.M610577200, ISSN: 0021-9258.

Panizzi P, Boxrud PD, Verhamme IM, Bock PE. Binding of the COOH-terminal lysine residue of streptokinase to plasmin(ogen) kringles enhances formation of the streptokinase.plasmin(ogen) catalytic complexes. J. Biol. Chem [print-electronic]. 2006 Sep 9/15/2006; 281(37): 26774-8. PMID: 16857686, PMCID: PMC2291350, PII: C600171200, DOI: 10.1074/jbc.C600171200, ISSN: 0021-9258.

Panizzi P, Friedrich R, Fuentes-Prior P, Kroh HK, Briggs J, Tans G, Bode W, Bock PE. Novel fluorescent prothrombin analogs as probes of staphylocoagulase-prothrombin interactions. J. Biol. Chem [print-electronic]. 2006 Jan 1/13/2006; 281(2): 1169-78. PMID: 16230340, PMCID: PMC2292460, PII: M507955200, DOI: 10.1074/jbc.M507955200, ISSN: 0021-9258.

Panizzi P, Friedrich R, Fuentes-Prior P, Richter K, Bock PE, Bode W. Fibrinogen substrate recognition by staphylocoagulase.(pro)thrombin complexes. J. Biol. Chem [print-electronic]. 2006 Jan 1/13/2006; 281(2): 1179-87. PMID: 16230339, PMCID: PMC2291351, PII: M507956200, DOI: 10.1074/jbc.M507956200, ISSN: 0021-9258.

Bianchini EP, Orcutt SJ, Panizzi P, Bock PE, Krishnaswamy S. Ratcheting of the substrate from the zymogen to proteinase conformations directs the sequential cleavage of prothrombin by prothrombinase. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2005 Jul 7/19/2005; 102(29): 10099-104. PMID: 16006504, PMCID: PMC1174926, PII: 0504704102, DOI: 10.1073/pnas.0504704102, ISSN: 0027-8424.

Ogawa T, Verhamme IM, Sun MF, Bock PE, Gailani D. Exosite-mediated substrate recognition of factor IX by factor XIa. The factor XIa heavy chain is required for initial recognition of factor IX. J. Biol. Chem [print-electronic]. 2005 Jun 6/24/2005; 280(25): 23523-30. PMID: 15829482, PMCID: PMC2292466, PII: M500894200, DOI: 10.1074/jbc.M500894200, ISSN: 0021-9258.

Bean RR, Verhamme IM, Bock PE. Role of the streptokinase alpha-domain in the interactions of streptokinase with plasminogen and plasmin. J. Biol. Chem [print-electronic]. 2005 Mar 3/4/2005; 280(9): 7504-10. PMID: 15623524, PMCID: PMC2292463, PII: M411637200, DOI: 10.1074/jbc.M411637200, ISSN: 0021-9258.

Panizzi P, Friedrich R, Fuentes-Prior P, Bode W, Bock PE. The staphylocoagulase family of zymogen activator and adhesion proteins. Cell. Mol. Life Sci. 2004 Nov; 61(22): 2793-8. PMID: 15558209, PMCID: PMC2291352, DOI: 10.1007/s00018-004-4285-7, ISSN: 1420-682X.

Boxrud PD, Verhamme IM, Bock PE. Resolution of conformational activation in the kinetic mechanism of plasminogen activation by streptokinase. J. Biol. Chem [print-electronic]. 2004 Aug 8/27/2004; 279(35): 36633-41. PMID: 15215240, PII: M405264200, DOI: 10.1074/jbc.M405264200, ISSN: 0021-9258.

Boxrud PD, Bock PE. Coupling of conformational and proteolytic activation in the kinetic mechanism of plasminogen activation by streptokinase. J. Biol. Chem [print-electronic]. 2004 Aug 8/27/2004; 279(35): 36642-9. PMID: 15215239, PII: M405265200, DOI: 10.1074/jbc.M405265200, ISSN: 0021-9258.

Verhamme IM, Bock PE, Jackson CM. The preferred pathway of glycosaminoglycan-accelerated inactivation of thrombin by heparin cofactor II. J. Biol. Chem [print-electronic]. 2004 Mar 3/12/2004; 279(11): 9785-95. PMID: 14701814, PII: M313962200, DOI: 10.1074/jbc.M313962200, ISSN: 0021-9258.

Anderson PJ, Bock PE. Role of prothrombin fragment 1 in the pathway of regulatory exosite I formation during conversion of human prothrombin to thrombin. J. Biol. Chem [print-electronic]. 2003 Nov 11/7/2003; 278(45): 44489-95. PMID: 12939270, PII: M306916200, DOI: 10.1074/jbc.M306916200, ISSN: 0021-9258.

Anderson PJ, Nesset A, Bock PE. Effects of activation peptide bond cleavage and fragment 2 interactions on the pathway of exosite I expression during activation of human prethrombin 1 to thrombin. J. Biol. Chem [print-electronic]. 2003 Nov 11/7/2003; 278(45): 44482-8. PMID: 12939269, PII: M306917200, DOI: 10.1074/jbc.M306917200, ISSN: 0021-9258.

Bedsted T, Swanson R, Chuang YJ, Bock PE, Björk I, Olson ST. Heparin and calcium ions dramatically enhance antithrombin reactivity with factor IXa by generating new interaction exosites. Biochemistry. 2003 Jul 7/15/2003; 42(27): 8143-52. PMID: 12846563, DOI: 10.1021/bi034363y, ISSN: 0006-2960.

Flanagan JJ, Chen JC, Miao Y, Shao Y, Lin J, Bock PE, Johnson AE. Signal recognition particle binds to ribosome-bound signal sequences with fluorescence-detected subnanomolar affinity that does not diminish as the nascent chain lengthens. J. Biol. Chem [print-electronic]. 2003 May 5/16/2003; 278(20): 18628-37. PMID: 12621052, PII: M300173200, DOI: 10.1074/jbc.M300173200, ISSN: 0021-9258.

Verhamme IM, Olson ST, Tollefsen DM, Bock PE. Binding of exosite ligands to human thrombin. Re-evaluation of allosteric linkage between thrombin exosites I and II. J. Biol. Chem [print-electronic]. 2002 Mar 3/1/2002; 277(9): 6788-98. PMID: 11724802, PII: M110257200, DOI: 10.1074/jbc.M110257200, ISSN: 0021-9258.

Anderson PJ, Bock PE. Biotin derivatives of D-Phe-Pro-Arg-CH2Cl for active-site-specific labeling of thrombin and other serine proteinases. Anal. Biochem. 2001 Sep 9/15/2001; 296(2): 254-61. PMID: 11554721, PII: S0003-2697(01)95302-3, DOI: 10.1006/abio.2001.5302, ISSN: 0003-2697.

Boxrud PD, Verhamme IM, Fay WP, Bock PE. Streptokinase triggers conformational activation of plasminogen through specific interactions of the amino-terminal sequence and stabilizes the active zymogen conformation. J. Biol. Chem [print-electronic]. 2001 Jul 7/13/2001; 276(28): 26084-9. PMID: 11369771, PII: M101966200, DOI: 10.1074/jbc.M101966200, ISSN: 0021-9258.

Pekovich SR, Bock PE, Hoover RL. Thrombin-thrombomodulin activation of protein C facilitates the activation of progelatinase A. FEBS Lett. 2001 Apr 4/6/2001; 494(1-2): 129-32. PMID: 11297749, PII: S0014-5793(01)02296-7, ISSN: 0014-5793.

Johnson AE, Chen JC, Flanagan JJ, Miao Y, Shao Y, Lin J, Bock PE. Structure, function, and regulation of free and membrane-bound ribosomes: the view from their substrates and products. Cold Spring Harb. Symp. Quant. Biol. 2001; 66: 531-41. PMID: 12762055, ISSN: 0091-7451.

Monteiro, R. Q., Bock, P. E., Bianconi, M. L., and Zingali, R. B. Characterization of Bothrojaracin Interacion with Human Prothrombin. Protein Science. 2001; 10: 1897-904.

Boxrud PD, Bock PE. Streptokinase binds preferentially to the extended conformation of plasminogen through lysine binding site and catalytic domain interactions. Biochemistry. 2000 Nov 11/14/2000; 39(45): 13974-81. PMID: 11076540, PII: bi000594i, ISSN: 0006-2960.

Anderson PJ, Nesset A, Dharmawardana KR, Bock PE. Role of proexosite I in factor Va-dependent substrate interactions of prothrombin activation. J. Biol. Chem. 2000 Jun 6/2/2000; 275(22): 16435-42. PMID: 10748008, PII: M001255200, DOI: 10.1074/jbc.M001255200, ISSN: 0021-9258.

Anderson PJ, Nesset A, Dharmawardana KR, Bock PE. Characterization of proexosite I on prothrombin. J. Biol. Chem. 2000 Jun 6/2/2000; 275(22): 16428-34. PMID: 10748007, PII: M001254200, DOI: 10.1074/jbc.M001254200, ISSN: 0021-9258.

Boxrud PD, Fay WP, Bock PE. Streptokinase binds to human plasmin with high affinity, perturbs the plasmin active site, and induces expression of a substrate recognition exosite for plasminogen. J. Biol. Chem. 2000 May 5/12/2000; 275(19): 14579-89. PMID: 10799544, PII: 275/19/14579, ISSN: 0021-9258.

Dharmawardana KR, Olson ST, Bock PE. Role of regulatory exosite I in binding of thrombin to human factor V, factor Va, factor Va subunits, and activation fragments. J. Biol. Chem. 1999 Jun 6/25/1999; 274(26): 18635-43. PMID: 10373475, ISSN: 0021-9258.

Dharmawardana KR, Bock PE. Demonstration of exosite I-dependent interactions of thrombin with human factor V and factor Va involving the factor Va heavy chain: analysis by affinity chromatography employing a novel method for active-site-selective immobilization of serine proteinases. Biochemistry. 1998 Sep 9/22/1998; 37(38): 13143-52. PMID: 9748321, PII: bi9812165, DOI: 10.1021/bi9812165, ISSN: 0006-2960.

Bock PE, Olson ST, Björk I. Inactivation of thrombin by antithrombin is accompanied by inactivation of regulatory exosite I. J. Biol. Chem. 1997 Aug 8/8/1997; 272(32): 19837-45. PMID: 9242645, ISSN: 0021-9258.

Hogg PJ, Jackson CM, Labanowski JK, Bock PE. Binding of fibrin monomer and heparin to thrombin in a ternary complex alters the environment of the thrombin catalytic site, reduces affinity for hirudin, and inhibits cleavage of fibrinogen. J. Biol. Chem. 1996 Oct 10/18/1996; 271(42): 26088-95. PMID: 8824251, ISSN: 0021-9258.

Bock PE, Day DE, Verhamme IM, Bernardo MM, Olson ST, Shore JD. Analogs of human plasminogen that are labeled with fluorescence probes at the catalytic site of the zymogen. Preparation, characterization, and interaction with streptokinase. J. Biol. Chem. 1996 Jan 1/12/1996; 271(2): 1072-80. PMID: 8557633, ISSN: 0021-9258.

Olson ST, Bock PE, Kvassman J, Shore JD, Lawrence DA, Ginsburg D, Björk I. Role of the catalytic serine in the interactions of serine proteinases with protein inhibitors of the serpin family. Contribution of a covalent interaction to the binding energy of serpin-proteinase complexes. J. Biol. Chem. 1995 Dec 12/15/1995; 270(50): 30007-17. PMID: 8530403, ISSN: 0021-9258.

Olson ST, Stephens AW, Hirs CH, Bock PE, Björk I. Kinetic characterization of the proteinase binding defect in a reactive site variant of the serpin, antithrombin. Role of the P1' residue in transition-state stabilization of antithrombin-proteinase complex formation. J. Biol. Chem. 1995 Apr 4/28/1995; 270(17): 9717-24. PMID: 7730349, ISSN: 0021-9258.

Bock PE. Thioester peptide chloromethyl ketones: reagents for active site-selective labeling of serine proteinases with spectroscopic probes. Meth. Enzymol. 1993; 222: 478-503. PMID: 8412811, PII: 0076-6879(93)22030-J, ISSN: 0076-6879.

Björk I, Ylinenjärvi K, Olson ST, Bock PE. Conversion of antithrombin from an inhibitor of thrombin to a substrate with reduced heparin affinity and enhanced conformational stability by binding of a tetradecapeptide corresponding to the P1 to P14 region of the putative reactive bond loop of the inhibitor. J. Biol. Chem. 1992 Jan 1/25/1992; 267(3): 1976-82. PMID: 1730729, ISSN: 0021-9258.

Olson ST, Bock PE, Sheffer R. Quantitative evaluation of solution equilibrium binding interactions by affinity partitioning: application to specific and nonspecific protein-heparin interactions. Arch. Biochem. Biophys. 1991 May 5/1/1991; 286(2): 533-45. PMID: 1897976, ISSN: 0003-9861.

Carlisle TL, Bock PE, Jackson CM. Kinetic intermediates in prothrombin activation. Bovine prethrombin 1 conversion to thrombin by factor X. J. Biol. Chem. 1990 Dec 12/15/1990; 265(35): 22044-55. PMID: 2254347, ISSN: 0021-9258.

Bock PE, Craig PA, Olson ST, Singh P. Isolation of human blood coagulation alpha-factor Xa by soybean trypsin inhibitor-sepharose chromatography and its active-site titration with fluorescein mono-p-guanidinobenzoate. Arch. Biochem. Biophys. 1989 Sep; 273(2): 375-88. PMID: 2774557, ISSN: 0003-9861.

Shore JD, Day DE, Bock PE, Olson ST. Acceleration of surface-dependent autocatalytic activation of blood coagulation factor XII by divalent metal ions. Biochemistry. 1987 Apr 4/21/1987; 26(8): 2250-8. PMID: 3113477, ISSN: 0006-2960.

Available Postdoctoral Position Details
Posted: 7/23/2014
BLOOD COAGULATION ENZYMOLOGY
A Postdoctoral Research position is available to investigate the mechanisms and regulation of blood coagulation and
fibrinolysis reactions with protein chemistry, enzyme kinetics, and fluorescence spectroscopy approaches. Applicants
must be US citizens or permanent residents. Interested individuals who are recent Ph.D. degree graduates in biochemistry, biophysics,
chemistry, or biology should send a copy of their curriculum vitae and arrange for two letters of recommendation to be
sent to:Dr. Paul E. BOCK Vanderbilt University School of Medicine Department of Pathology
C-3321A Medical Center North Nashville, TN 37232-2561 Tel. (615)343-9863