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Journal of Lipid Research, Vol 37, 1786-1801, Copyright © 1996 by Lipid Research, Inc.
C Edelstein, JA Italia, O Klezovitch and AM Scanu
We have previously shown that a functional free apolipoprotein[a] (apo[a])
can be isolated from its parent lipoprotein[a] (Lp[a]) by a mild reductive
procedure. To shed further light on the properties of Lp[a] and apo[a] we
subjected them to a limited proteolysis by porcine pancreatic elastase.
This enzyme cleaved both at the Ile3520-Leu3521 bond in the linker between
kringles IV-4 and IV-5 of apo[a] generating two fragments F1 and F2. In
contrast to F1, which represented the N- terminal portion of apo[a] and was
functionally inert, F2, representing the C-terminal domain, bound to
lysine-Sepharose, fibrinogen, and fibronectin and formed a miniLp[a]
particle when incubated with LDL. The proteolytic pattern by pancreatic
elastase was also exhibited by human leukocyte elastase. F1, injected
intravenously into normal mice, was rapidly cleared (Ty2, 2.9 h) and after
1 h fragments in the size range of 100-33 kDa were observed in the urine.
In turn, F2 had a longer residence time (Ty2, 5 h) and was excreted in the
urine only after 5 h as fragments of 70-45 kDa. Fragments in the same size
range as found after F1 injection were also present in the urine after
injection of apo[a] or Lp[a]. Moreover, apo[a] fragments of the size seen
in mouse urine were spontaneously present in normal human urine and
appeared derived from larger apo[a] fragments in the plasma. Our results
indicate that enzymes of the elastase family cleave human apo[a] in vitro
into two main fragments that differ in structural and functional properties
and metabolic behavior. The comparable size of apo[a] fragments observed in
the urine of humans and injected mice invites the speculation that enzymes
of the elastase family may play a role in the biology of Lp[a] in vivo.
ARTICLES
Functional and metabolic differences between elastase-generated fragments of human lipoprotein[a] and apolipoprotein[a]
Department of Medicine, University of Chicago, IL 60637, USA.
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