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Plasmin Can Reduce the Function of Human  2
Glycoprotein I by Cleaving Domain V Into a Nicked Form
Naoki Ohkura,
Yoshihisa Hagihara,
Tetsuro Yoshimura,
Yuji Goto, and
Hisao Kato
From the Graduate School of Science, Osaka University, Toyonaka,
Osaka; Faculty of Engineering, Mie University, Tsu; and National
Cardiovascular Center Research Institute, Suita, Osaka, Japan.
 2-Glycoprotein I (2GPI)
is a highly glycosylated plasma protein with the ability to bind
negatively charged substances such as DNA, heparin, dextran sulfate,
and negatively charged phospholipids. The most relevant physiological
role of 2GPI is supposed to be the regulation of the
function of anionic phospholipids like cardiolipin (CL).
2GPI consists of a single polypeptide chain (326 amino acid residues) with a molecular mass of about 50 kD and
with five tandem repeated domains (I, II, III, IV, and V). In the
previous study, we found that factor Xa can produce the nicked form by cleaving Lys 317-Thr 318, using recombinant human domain V (r-Domain V). However, the reaction was extremely slow. In the present paper, we
found that plasmin can produce the nicked form of domain V, using
recombinant domain V (r-Domain V) and 2GPI from human
plasma. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, r-Domain V was rapidly cleaved into a nicked form by plasmin, very
slowly by factor Xa, but not by thrombin, tissue-type plasminogen activator, urokinase, and tissue factor/factor VIIa. The cleavage site
of r-Domain V and 2GPI by plasmin was proved to be Lys
317-Thr 318 by amino acid sequence analysis of the digest and of the
C-terminal peptide isolated by high-performance liquid chromatography.
The cleavage was completely inhibited by plasmin inhibitor
( 2PI). The nicked form was demonstrated to show reduced
affinity for CL with a dissociation constant of one order of magnitude
larger than that of the intact 2GPI. To determine
whether the specific cleavage of 2GPI by plasmin can
occur also in plasma, human plasma was first acid-treated to inactivate
2PI and then incubated with urokinase. About 12% of
2GPI in plasma was nicked when 2PI
activity decreased to 80%. The nicked form was not generated in
plasminogen-depleted plasma. These results suggest that plasmin can
produce the nicked form of 2GPI with the reduced ability
to bind phospholipids in vivo.
Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4173-4179
© 1998 by The American Society of Hematology.
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