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A synthetic peptide derived from staphylokinase enhances plasminogen activation by tissue‐type plasminogen activator
Author(s) -
OKADA K.,
UESHIMA S.,
MATSUNO H.,
NAGAI N.,
KAWAO N.,
TANAKA M.,
MATSUO O.
Publication year - 2011
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2011.04257.x
Subject(s) - staphylokinase , plasminogen activator , tissue plasminogen activator , peptide , chemistry , fibrinolysis , biochemistry , medicine , recombinant dna , gene
Summary. Background: A synthetic nonadecapeptide (SP; GPYLMVNVTGVDGKGNELL) previously enhanced the activation of plasminogen by the SAK/plasmin complex. Objectives: To identify the binding site for SP on plasminogen and elucidate the effects of SP on plasminogen activation by the tissue‐type plasminogen activator (t‐PA). Methods: The effects of SP on plasminogen activation were estimated using a chromogenic substrate and from the cleavage of plasmin on SDS‐PAGE under reduced conditions. The binding to SP of various peptides derived from the amino acid sequence of plasminogen was analyzed with an IAsys biosensor. The SP‐mediated structural change to plasminogen was analyzed by circular dichroism (CD) spectroscopy. The thrombolytic effects of SP were examined using a mouse model of thrombosis. Results: SP enhanced the activation of plasminogen by t‐PA. The catalytic efficiency ( k cat / K m ) of Glu‐plasminogen activation by t‐PA was 11.4‐fold higher in the presence than absence of SP. The binding of SP to plasminogen was greatly inhibited by a synthetic peptide, FEKDKYILQGVTSWGLG, located close to the C‐terminal of the plasminogen B region. Near‐ultraviolet CD spectra of the complex between SP and Glu‐plasminogen significantly differed from those of Glu‐plasminogen. When SP was administered in a mouse model of thrombosis, early recanalization was observed in a dose‐dependent manner. However, SP did not cause recanalization in t‐PA gene‐deficient mice. Conclusions: SP bound to the B region and promoted the activation of plasminogen by t‐PA, and then induced effective thrombolysis.