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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
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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
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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
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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
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