Susan C. Bock
Professor of Medicine and of Bioengineering and of Medicinal Chemistry
B.S. Massachusetts Institute of Technology
Ph.D. University of California, Irvine
Susan Bock's Lab Page
Susan Bock's PubMed Literature Search
Research
We study antithrombin III (ATIII) structure-function relationships in order to better understand the anticoagulant and anti-inflammatory properties 0f this essential glycoprotein. This work has also enabled us to develop recombinant ATIIIs that are superior to the endogenous molecule with respect to functional half-life under inflammatory conditions and more efficient loading onto vascular surfaces.
Heparin-mediated and Cofactor-independent Conformational Activation of Antithrombin III In blood there is an equilibrium between an inactive native ATIII conformation that has its reactive center loop partially inserted into beta-sheet A, and a loop-expelled conformation that reacts rapidly with target enzymes. The population of inactive molecules greatly exceeds that of active molecules in the absence of pharmaceutical or vascular surface heparins. However, ATIII may be fully activated by heparin cofactor binding, which initiates protein conformational changes leading to loop expulsion. The goal of this project is to improve understanding of the mechanisms underlying uncatalyzed and heparin-dependent ATIII activation by identifying structural elements that stabilize the native and activated conformations, and determining how these interactions are switched on and off during the uncatalyzed equilibrium and by heparin cofactor binding. For example, recent work demonstrates that concurrent disruption of helix D – strand 2A and reactive center loop native structural constraints activates antithrombin to that same degree as heparin cofactor binding.
ATIII Targeting to Vascular and Biomaterial Surfaces The antithrombotic and the anti-inflammatory actions of antithrombin III are mediated through its binding to pentasaccharide-bearing heparan sulfate proteoglycans on vascular surfaces. To more effectively control pathological thrombotic and inflammatory processes which are initiated and propagated on vascular and biomaterial surfaces, we have modified (1) ATIII mass transport properties to increase surface loading by a factor of 7, and (2) ATIII neutrophil elastase cleavage and inactivation sensitivity to increase functional half-life by a factor of 10. Recombinant “super beta” antithrombin is a more efficient antithrombotic than endogenous, plasma-derived ATIII, doubling the time to occlusion in a rabbit ferric chloride - induced arterial thrombosis model. The anti-inflamatory and anticoagulant properties of super beta antithrombins are also being evaluated in ischemia/reperfusion injury models in which plasma-derived antithrombin has exhibited protective effects, but required supraphysiological doses.
References
1. Dela Cruz RG, Jairajpuri MA, Bock SC (2006) Disruption of a tight cluster surrounding tyrosine-131 in the native conformation of antithrombin III activates it for factor Xa inhibition. J Biol Chem. 281:31668-31676
2. Bock SC, Picard V, Zendehrouh P (2005) Human Antithrombin IIIs and Methods Related Thereto. U.S. Patent #6,878,813
3. Bock SC (2005) Antithrombin III and Heparin Cofactor II. Chapter 13 in Hemostasis and Thrombosis, Basic Principles and Clinical Practice , 5th edition. R.W. Colman et al., eds. J.B. Lippincott, Philadelphia
4. Schedin-Weiss S, Desai UR, Bock SC, Olson ST, Björk I (2004) Roles of N-terminal region residues Lys11, Arg13 and Arg24 of antithrombin in heparin recognition and in promotion and stabilization of the heparin-induced conformational change. Biochemistry 43:675-83
5. Jairajpuri MA, Lu A, Desai U, Olson ST, Bjork I, Bock SC (2003) Antithrombin III phenylalanines 122 and 121 contribute to its high affinity for heparin and its conformational activation. J. Biol. Chem. 278:15941-50
6. Schedin-Weiss S, Desai UR, Bock SC, Gettins PGW, Olson ST, Bjork I (2002) The Importance of Lysine 125 for Heparin Binding and Activation of Antithrombin. Biochemistry 15:4779-4788
7. Chuang YJ, Richard Swanson R, Raja SM, Bock SC, Olson ST (2001) The Antithrombin P1 Residue Is Important for Target Proteinase Specificity but Not for Heparin Activation of the Serpin. Characterization of P1 Antithrombin Variants with Altered Proteinase Specificity but Normal Heparin Activation. Biochemistry 40:6670-6679
8. Bock SC (2001) Antithrombin III and Heparin Cofactor II. Chapter 14 in Hemostasis and Thrombosis, Basic Principles and Clinical Practice, 4th edition. R.W. Colman, J. Hirsh, V.J. Marder, A.W. Clowes, J.N. George, eds. J.B. Lippincott, Philadelphia
9. Desai U, Swanson R, Bock SC, Bjork I, Olson ST (2000) Role of Arginine 129 in Heparin Binding and Activation of Antithrombin. J. Biol. Chem. 275:18976-84
10. Arocas V, Turk B, Bock SC, Olson ST, Bjork I (2000) The Region of Antithrombin Interacting with Full-Length Heparin Chains Outside the High-Affinity Pentasaccharide Sequence Extends to Lys 136 But Not to Lys 139. Biochemistry 39:8512-8
