Mechanism of plasmin generation by S100A10

Victoria A. Miller; Patricia A. Madureira; Ain Adilliah Kamaludin; Jeffrey Komar; Vandna Sharma; Girish Sahni; Craig Thelwell; Colin Longstaff; David M. Waisman

doi:10.1160/TH16-12-0936

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2017; 117(06): 1058-1071
DOI: 10.1160/TH16-12-0936

Coagulation and Fibrinolysis

Schattauer GmbH

Mechanism of plasmin generation by S100A10

Victoria A. Miller

¹Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada

,

Patricia A. Madureira

²Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas, Faro, Portugal

,

Ain Adilliah Kamaludin

³Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada

,

Jeffrey Komar

³Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada

,

Vandna Sharma

⁴Institute of Microbial Technology (C. S. I.R), Sector 39-A, Chandigarh, India

,

Girish Sahni

⁴Institute of Microbial Technology (C. S. I.R), Sector 39-A, Chandigarh, India

,

Craig Thelwell

⁵Haemostasis Section, Biotherapeutics Group, National Institute for Biological Standards and Control, South Mimms, Herts, UK

,

Colin Longstaff

⁵Haemostasis Section, Biotherapeutics Group, National Institute for Biological Standards and Control, South Mimms, Herts, UK

,

David M. Waisman

¹Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada

³Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada

› Author Affiliations

Abstract

Summary

Plasminogen (Pg) is cleaved to form plasmin by the action of specific plasminogen activators such as the tissue plasminogen activator (tPA). Although the interaction of tPA and Pg with the surface of the fibrin clot has been well characterised, their interaction with cell surface Pg receptors is poorly understood. S100A10 is a cell surface Pg receptor that plays a key role in cellular plasmin generation. In the present report, we have utilised domain-switched/deleted variants of tPA, truncated plasminogen variants and S100A10 site-directed mutant proteins to define the regions responsible for S100A10-dependent plasmin generation. In contrast to the established role of the finger domain of tPA in fibrin-stimulated plasmin generation, we show that the kringle-2 domain of tPA plays a key role in S100A10-dependent plasmin generation. The kringle-1 domain of plasminogen, indispensable for fibrin-binding, is also critical for S100A10-dependent plasmin generation. S100A10 retains activity after substitution or deletion of the carboxyl-terminal lysine suggesting that internal lysine residues contribute to its plasmin generating activity. These studies define a new paradigm for plasminogen activation by the plasminogen receptor, S100A10.

Keywords

S100A10 - annexin A2 - plasminogen - plasmin - tissue plasminogen activator - plasminogen regulation

Full Text

References

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