|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1714-1720
Regulation of factor VIIIa by human activated protein C and
protein S: inactivation of cofactor in the intrinsic factor
Xase
Lynn M. O'Brien,
Maria Mastri, and
Philip J. Fay
From the Departments of Medicine and Biochemistry and Biophysics,
University of Rochester School of Medicine, and the Department of
Chemistry, Nazareth College, Rochester, NY
Factor VIIIa is a trimer of A1, A2, and A3-C1-C2 subunits.
Inactivation of the cofactor by human activated protein C (APC) results
from preferential cleavage at Arg336 within the A1 subunit, followed by
cleavage at Arg562 bisecting the A2 subunit. In the presence of human
protein S, the rate of APC-dependent factor VIIIa inactivation
increased several-fold and correlated with an increased rate of
cleavage at Arg562. (Active site-modified) factor IXa, blocked cleavage
at the A2 site. However, APC-catalyzed inactivation of factor VIIIa
proceeded at a similar rate independent of factor IXa, consistent with
the location of the preferential cleavage site within the A1 subunit.
Addition of protein S failed to increase the rate of cleavage at the A2
site when factor IXa was present. In the presence of factor X, cofactor
inactivation was inhibited, due to a reduced rate of cleavage at
Arg336. However, inclusion of protein S restored near original rates of
factor VIIIa inactivation and cleavage at the A1 site, thus overcoming the factor X-dependent protective effect. These results suggest that in
the human system, protein S stimulates APC-catalyzed factor VIIIa
inactivation by facilitating cleavage of A2 subunit (an effect retarded
in the presence of factor IXa), as well as abrogating protective
interactions of the cofactor with factor X.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
K. Nogami, K. Nishiya, E. L. Saenko, M. Takeyama, K. Ogiwara, A. Yoshioka, and M. Shima
Identification of Plasmin-interactive Sites in the Light Chain of Factor VIII Responsible for Proteolytic Cleavage at Lys36
J. Biol. Chem.,
March 13, 2009;
284(11):
6934 - 6945.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Gale, T. J. Cramer, D. Rozenshteyn, and J. R. Cruz
Detailed Mechanisms of the Inactivation of Factor VIIIa by Activated Protein C in the Presence of Its Cofactors, Protein S and Factor V
J. Biol. Chem.,
June 13, 2008;
283(24):
16355 - 16362.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Nogami, M. Shima, T. Matsumoto, K. Nishiya, I. Tanaka, and A. Yoshioka
Mechanisms of Plasmin-catalyzed Inactivation of Factor VIII: A CRUCIAL ROLE FOR PROTEOLYTIC CLEAVAGE AT Arg336 RESPONSIBLE FOR PLASMIN-CATALYZED FACTOR VIII INACTIVATION
J. Biol. Chem.,
February 23, 2007;
282(8):
5287 - 5295.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. M. Hackeng, K. M. Sere, G. Tans, and J. Rosing
Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor
PNAS,
February 28, 2006;
103(9):
3106 - 3111.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Rezende, R. E. Simmonds, and D. A. Lane
Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex
Blood,
February 15, 2004;
103(4):
1192 - 1201.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Manithody, P. J. Fay, and A. R. Rezaie
Exosite-dependent regulation of factor VIIIa by activated protein C
Blood,
June 15, 2003;
101(12):
4802 - 4807.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. K. Giri, S. Linse, P. G. de Frutos, T. Yamazaki, B. O. Villoutreix, and B. Dahlback
Structural Requirements of Anticoagulant Protein S for Its Binding to the Complement Regulator C4b-binding Protein
J. Biol. Chem.,
April 19, 2002;
277(17):
15099 - 15106.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. E. K. Rosenblum, K. Schmidt, J. Freas, M. Mastri, and P. J. Fay
Cofactor Activities of Factor VIIIa and A2 Subunit following Cleavage of A1 Subunit at Arg336
J. Biol. Chem.,
March 29, 2002;
277(14):
11664 - 11669.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Riewald and W. Ruf
Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor
PNAS,
July 3, 2001;
98(14):
7742 - 7747.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
