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ATVB In Focus Tissue Factor: Past, Present, and Future Series Editor: Nigel Mackman and Mark B. Taubman What Is Wrong With the Allosteric Disulfide Bond Hypothesis? Ronald R. Bach, Dougald Monroe I Downloaded from http://atvb.ahajournals.org/ by guest on August 3, 2017 nitial models of coagulation postulated a strict separation of the initiator of coagulation, tissue factor (TF), from the coagulation factors in blood. More recent studies have shown low but detectable levels of TF in blood1 (reviewed in2). This suggests that TF activity is under some level of control beyond simple expression levels. One mechanism of control is suggested by the observation from cell culture studies that TF activity on cells can be rapidly and substantially increased without significant changes in TF antigen.3 TF with reduced activity has been referred to as encrypted. The evidence supporting TF encryption and decryption has been dealt with in a previous review.2 It has been proposed that chemical reactions involving two half-cystines in the extracellular domain of tissue factor, cys186 and cys209, are the key events regulating TF procoagulant and signaling functions.4 – 8 According to the allosteric disulfide bond hypothesis, when the side chains are reduced TF is inactive/encrypted. When the sulfhydryls are oxidized, the resulting disulfide bond formation induces a conformational change that converts TF to a procoagulant/decrypted state. Some of the literature has proposed that protein disulfide isomerase (PDI) is responsible for the oxidation step.5 After three years there is still no direct quantitative evidence for free thiols in TF. In tissue culture studies, both oxidizing and reducing agents can promote TF decryption.9 Further, studies on PDI have suggested that lipid contamination of the protein might account for the TF decryption observed in some studies.10 More problematic is the issue of accessibility. Are the half-cystines available for the proposed redox reactions? This is a relevant question because the half-cystines are buried deep within complex when activated factor VII (FVIIa) binds to the extracellular domain of TF11 (see Figure). Direct binding studies have established that encrypted TF and decrypted TF form stable high-affinity associations with FVII and FVIIa.12–14 All the observed dissociation constants are well below the plasma concentration of FVII. Also, there is sufficient extravascular FVII/FVIIa to saturate TF on perivascular cells even in the absence of injury.15 Finally, Figure. Disulfide 186 to 209 is masked by FVIIa binding to TF. The left panel shows TF in blue with the cys186– cys209 disulfide shown in yellow. The right panel shows TF in the same orientation with FVIIa shown in red. The model was constructed from the 1DAN submission11 to the Protein Data Bank16 using the program Pymol.17 during the ionophore-induced conversion of encrypted TFFVIIa to decrypted TF-FVIIa the enzyme remains bound to the cofactor.3 This body of evidence supports the conclusion that FVII/FVIIa is bound to essentially all the TF molecules on cells in blood and the surrounding vessel wall. Therefore, cys186 and cys209 are not available to interact with PDI or even participate in the proposed reactions. Disclosures None. References 1. Giesen PL, Rauch U, Bohrmann B, Kling D, Roque M, Fallon JT, Badimon JJ, Himber J, Riederer MA, Nemerson Y. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci U S A. 1999;96: 2311–2315. 2. Bach RR. Tissue factor encryption. Arterioscler Thromb Vasc Biol. 2006; 26:456 – 461. 3. Bach RR, Moldow CF. Mechanism of tissue factor activation on HL-60 cells. Blood. 1997;89:3270 –3276. 4. Chen VM, Ahamed J, Versteeg HH, Berndt MC, Ruf W, Hogg PJ. Evidence for activation of tissue factor by an allosteric disulfide bond. Biochemistry. 2006;45:12020 –12028. Received October 7, 2009; revision accepted October 15, 2009. From the VA Medical Center (R.R.B.), Minneapolis, Minn; and the University of North Carolina (D.M.), Chapel Hill. Correspondence to Dr Ronald R. Bach, VA Medical Center, Research Service (151), 1 Veterans Dr, Minneapolis, MN 55417. E-mail [email protected] (Arterioscler Thromb Vasc Biol. 2009;29:1997-1998.) © 2009 American Heart Association, Inc. Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.109.194985 1997 1998 Arterioscler Thromb Vasc Biol December 2009 5. Ahamed J, Versteeg HH, Kerver M, Chen VM, Mueller BM, Hogg PJ, Ruf W. Disulfide isomerization switches tissue factor from coagulation to cell signaling. Proc Natl Acad Sci U S A. 2006;103:13932–13937. 6. Camerer E, Trejo J. Cryptic messages: is noncoagulant tissue factor reserved for cell signaling? Proc Natl Acad Sci U S A. 2006;103: 14259 –13260. 7. Versteeg HH, Ruf W. Tissue factor coagulant function is enhanced by proteindisulfide isomerase independent of oxidoreductase activity. J Biol Chem. 2007;282:25416 –25424. 8. Chen VM, Hogg PJ. Allosteric disulfide bonds in thrombosis and thrombolysis. J Thromb Haemo. 2006;4:2533–2541. 9. Pendurthi UR, Ghosh S, Mandal SK, Rao LV. Tissue factor activation: is disulfide bond switching a regulatory mechanism? Blood. 2007;110: 3900 –3908. 10. Persson E. Protein disulfide isomerase has no stimulatory chaperone effect on factor X activation by factor VIIa-soluble tissue factor. Thromb Res. 2008;123:171–176. 11. Banner DW, D’Arcy A, Chene C, Winkler FK, Guha A, Konigsberg WH, Nemerson Y, Kirchhofer D. The crystal structure of the complex of blood 12. 13. 14. 15. 16. 17. coagulation factor VIIa with soluble tissue factor. Nature. 1996;380: 41– 46. Broze GJ Jr. Binding of human factor VII and VIIa to monocytes. J Clin Invest. 1982;70:526 –535. Le DT, Rapaport SI, Rao LV. Relations between factor VIIa binding and expression of factor VIIa/tissue factor catalytic activity on cell surfaces. J Biol Chem. 1992;267:15447–15454. Drake TA, Ruf W, Morrissey JH, Edgington TS. Functional tissue factor is entirely cell surface expressed on lipopolysaccharide-stimulated human blood monocytes and a constitutively tissue factor-producing neoplastic cell line. J Cell Biol. 1989;109:389 –395. Hoffman M, Colina CM, McDonald AG, Arepally GM, Pedersen L, Monroe DM. Tissue factor around dermal vessels has bound factor VII in the absence of injury. J Thromb Haemo. 2006;5:1403–1408. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE. The protein data bank. Nucleic Acids Res. 2000;28:235–242. DeLano W. The Pymol Molecular Graphics System. Palo Alto, Calif: DeLano Scientific; 2002. Downloaded from http://atvb.ahajournals.org/ by guest on August 3, 2017 Downloaded from http://atvb.ahajournals.org/ by guest on August 3, 2017 What Is Wrong With the Allosteric Disulfide Bond Hypothesis? Ronald R. Bach and Dougald Monroe Arterioscler Thromb Vasc Biol. 2009;29:1997-1998 doi: 10.1161/ATVBAHA.109.194985 Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2009 American Heart Association, Inc. All rights reserved. Print ISSN: 1079-5642. 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