ClfA221–550, a fibrinogen-binding segment of Staphylococcus aureus clumping factor A, disrupts fibrinogen function

Chao-Zong Liu; Mei-Hsu Shih; Pei-Jane Tsai

doi:10.1160/TH05-03-0205

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2005; 94(02): 286-294
DOI: 10.1160/TH05-03-0205

Theme Issue Article

Schattauer GmbH

ClfA_221–550, a fibrinogen-binding segment of Staphylococcus aureus clumping factor A, disrupts fibrinogen function

Chao-Zong Liu

¹Department of Pharmacology, College of Medicine, Tzu Chi University, Hualien, Taiwan

²Institute of Pharmacology and Toxicology, College of Life Sciences, Tzu Chi University, Hualien, Taiwan

,

Mei-Hsu Shih

³Department of Pharmacy, Buddhist Tzu Chi Shin Dian Hospital, Taipei County, Taiwan

,

Pei-Jane Tsai

⁴Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan

› Institutsangaben

Abstract

Summary

Clumping factor A (ClfA) is a surface of protein Staphylococcusaureus bacteria known for its ability to bind the C-terminus of plasma fibrinogen γ chain, which participates in mediating fibrinogen- platelet interaction and fibrin cross-linking, resulting in thrombus formation. With an aim to develop agents that block fibrinogen γ chain C-terminus,the fibrinogen-binding segment of ClfA locating at residues 221–550 was produced by recombinant technology and tested for its ability to inhibit platelet functions and fibrin clot formation. Recombinant ClfA_221–550 bound fibrinogen and blocked fibrinogen-platelet interaction, resulting in the inhibition of both ADP- and collagen-induced platelet aggregations. ClfA_221–550 also affected fibrin clot formation, in which factor XIIIa-mediated cross-linking of fibrinogen γ chains was abrogated by ClfA_221–550 leaving the release of fibrinopeptides A and B from fibrinogen by thrombin unaltered, indicating that ClfA_221–550 interfered with fibrin clot formation without affecting thrombin’s catalytic activity. Plateletmediated clot retraction depends on both platelet-fibrinogen interaction and fibrin clot formation, which makes platelet thrombus less susceptible to fibrinolysis. At the concentration that reduced platelet aggregation by 40%, ClfA_221–550 prevented platelet- mediated clot retraction, whereas the glycoprotein IIb/IIIa antagonist tirofiban needed a higher concentration in inhibiting clot retraction than inhibiting platelet aggregation. By virtue of the multiple effects of ClfA_221–550 on platelet aggregation, fibrin clot formation and platelet-mediated clot retraction,the binding of ClfA_221–550 to fibrinogen merits further investigation for its potential as a new antithrombotic agent.

Keywords

Fibrinogen - fibrinogen-binding protein - clumping factor A - antithrombosis

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Referenzen

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