Tài liệu Báo cáo khoa học: Control of the coagulation system by serpins Getting by with a little

MINIREVIEW

Control of the coagulation system by serpins

Getting by with a little help from glycosaminoglycans

Robert N. Pike1,2, Ashley M. Buckle1,2, Bernard F. le Bonniec3 and Frank C. Church4

1 Department of Biochemistry & Molecular Biology and Co-operative Research Centres for Vaccine Technology and Oral Health Sciences,

Monash University, Clayton, Victoria, Australia

2 The Victorian Bioinformatics Consortium, Monash University, Clayton, Victoria, Australia

3 INSERM U428, Faculte´ de Pharmacie, Universite´ Paris V, Paris, France

4 Departments of Pathology and Laboratory Medicine, Pharmacology, and Medicine, Carolina Cardiovascular Biology Center,

The University of North Carolina at Chapel Hill, School of Medicine, NC, USA

Introduction

Efficient functioning of the coagulation system is vital

to human health [1]. However, control of this system,

in particular its regulation to prevent inappropriate,

excessive or mislocalized clotting of blood, is also vital

to prevent cardiovascular diseases such as deep vein

thrombosis.

Because many of the principal procoagulant compo￾nents of the system are serine proteases, regulation of

the system is principally by the action of serine protease

inhibitors. One major class of serine protease inhibitors

regulating procoagulant enzymes is the serpin super￾family [2]. The principal inhibitor of procoagulant

enzymes such as thrombin and factor Xa is the serpin

antithrombin (AT). There are, however, other serpins

that act to control coagulation enzymes, such as heparin

cofactor II (HC-II), protease nexin I and C1-inhibitor.

Some serpins, such as protein C inhibitor (PCI), act to

control the action of anticoagulant enzymes, such as

activated protein C.

A feature of many of the serpins that control

enzymes in the coagulation system is that they them￾selves are under the control of glycosaminoglycans

Keywords

antithrombin; coagulation;

glycosaminoglycans; heparin cofactor II;

proteases; protein C inhibitor; serpins;

thrombin

Correspondence

R. N. Pike, Department of Biochemistry &

Molecular Biology, Monash University,

Clayton, Victoria 3800, Australia

Fax: +61 3 99054699

Tel: +61 3 99053923

E-mail: [email protected]

(Received 16 December 2004, accepted 14

July 2005)

doi:10.1111/j.1742-4658.2005.04880.x

Members of the serine protease inhibitor (serpin) superfamily play import￾ant roles in the inhibition of serine proteases involved in complex systems.

This is evident in the regulation of coagulation serine proteases, especially

the central enzyme in this system, thrombin. This review focuses on three

serpins which are known to be key players in the regulation of thrombin:

antithrombin and heparin cofactor II, which inhibit thrombin in its pro￾coagulant role, and protein C inhibitor, which primarily inhibits the throm￾bin ⁄thrombomodulin complex, where thrombin plays an anticoagulant

role. Several structures have been published in the past few years which

have given great insight into the mechanism of action of these serpins and

have significantly added to a wealth of biochemical and biophysical studies

carried out previously. A major feature of these serpins is that they are

under the control of glycosaminoglycans, which play a key role in acceler￾ating and localizing their action. While further work is clearly required

to understand the mechanism of action of the glycosaminoglycans, the bio￾logical mechanisms whereby cognate glycosaminoglycans for each serpin

come into contact with the inhibitors also requires much further work in

this important field.

Abbreviations

AT, antithrombin; GAG, glycosaminoglycan; HC-II, heparin cofactor II; PCI, protein C inhibitor; serpin, serine protease inhibitor.

4842 FEBS Journal 272 (2005) 4842–4851 ª 2005 FEBS