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J. Biol. Chem., Vol. 265, Issue 33, 20156-20159, Nov, 1990
T Hayashi, M Zushi, S Yamamoto and K Suzuki
To elucidate the binding sites for thrombin and protein C in the six
epidermal growth factor (EGF) domains of human thrombomodulin, recombinant
mutant proteins were expressed in COS-1 cells. Mutant protein EGF456, which
contains the fourth, fifth, and sixth EGF domains from the NH2 terminus of
thrombomodulin, showed complete cofactor activity in thrombin-catalyzed
protein C activation, as did intact thrombomodulin or elastase-digested
thrombomodulin. EGF56, containing the fifth and sixth EGF domains, did not
have cofactor activity; but EGF45, containing the fourth and fifth EGF
domains, had about one-tenth of the cofactor activity of EGF456. Thrombin
binding to attached recombinant thrombomodulin (D123) was inhibited by
EGF45 as well as by EGF56. A synthetic peptide (ECPEGYILDDGFICTDIDE),
corresponding to Glu- 408 to Glu-426 in the fifth EGF domain, inhibited
thrombin binding to attached thrombomodulin (D123) with an apparent Ki of
95 microM. At Ca2+ concentrations of 0.25-0.3 mM, intact protein C was
maximally activated by thrombin in the presence of EGF45, EGF456, or
EGF1-6, which contains the first to sixth EGF domains; but such maximum
cofactor activity was not observed when gamma-carboxyglutamic acid-
domainless protein C was used. These findings suggest that: 1) thrombin
binds to the latter half of the fifth EGF domain; and 2) protein C binds to
the fourth EGF domain of thrombomodulin through Ca2+ ions.
Further localization of binding sites for thrombin and protein C in human thrombomodulin
Division of Enzyme Cytology, University of Tokushima, Japan.
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