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Rational Design of Protein C Activators.
Barranco-Medina, Sergio; Murphy, Mary; Pelc, Leslie; Chen, Zhiwei; Di Cera, Enrico; Pozzi, Nicola.
Affiliation
  • Barranco-Medina S; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104 USA.
  • Murphy M; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104 USA.
  • Pelc L; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104 USA.
  • Chen Z; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104 USA.
  • Di Cera E; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104 USA.
  • Pozzi N; Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104 USA.
Sci Rep ; 7: 44596, 2017 03 15.
Article in En | MEDLINE | ID: mdl-28294177
ABSTRACT
In addition to its procoagulant and proinflammatory functions mediated by cleavage of fibrinogen and PAR1, the trypsin-like protease thrombin activates the anticoagulant protein C in a reaction that requires the cofactor thrombomodulin and the endothelial protein C receptor. Once in the circulation, activated protein C functions as an anticoagulant, anti-inflammatory and regenerative factor. Hence, availability of a protein C activator would afford a therapeutic for patients suffering from thrombotic disorders and a diagnostic tool for monitoring the level of protein C in plasma. Here, we present a fusion protein where thrombin and the EGF456 domain of thrombomodulin are connected through a peptide linker. The fusion protein recapitulates the functional and structural properties of the thrombin-thrombomodulin complex, prolongs the clotting time by generating pharmacological quantities of activated protein C and effectively diagnoses protein C deficiency in human plasma. Notably, these functions do not require exogenous thrombomodulin, unlike other anticoagulant thrombin derivatives engineered to date. These features make the fusion protein an innovative step toward the development of protein C activators of clinical and diagnostic relevance.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Recombinant Fusion Proteins / Protein C / Thrombomodulin / Protein C Deficiency Limits: Humans Language: En Journal: Sci Rep Year: 2017 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Recombinant Fusion Proteins / Protein C / Thrombomodulin / Protein C Deficiency Limits: Humans Language: En Journal: Sci Rep Year: 2017 Document type: Article