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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1058-1071
Number of pages14
JournalThrombosis and Haemostasis
Volume117
Issue number6
Early online date6 Apr 2017
DOIs
Publication statusPublished - 2 Jun 2017

Keywords

  • Annexin A2/genetics
  • Fibrin/metabolism
  • Fibrinolysin/metabolism
  • Humans
  • Kringles/genetics
  • Lysine/genetics
  • Mutagenesis, Site-Directed
  • Plasminogen/genetics
  • Protein Binding
  • Protein Engineering
  • Receptors, Cell Surface/genetics
  • S100 Proteins/genetics
  • Tissue Plasminogen Activator/genetics

Fingerprint

Dive into the research topics of 'Mechanism of plasmin generation by S100A10'. Together they form a unique fingerprint.

Cite this