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Volume 270,
Number 11,
Issue of March 17, 1995 pp. 6227-6234
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
Identification
of Two Functionally Distinct Lysine-binding Sites in Kringle 37 and in
Kringles 32 36 of Human Apolipoprotein(a)
(Received for publication, July 27, 1994; and in revised form, November 30, 1994)
Angelika
Ernst
,
Marion
Helmhold
,
Christoph
Brunner
,
Attila
Pethö-Schramm
,
Victor W.
Armstrong
,
Hans-Joachim
Müller
The well documented association between high plasma levels of
lipoprotein(a) (Lp(a)) and cardiovascular disease might be mediated by
the lysine binding of apolipoprotein(a) (apo(a)), the plasminogen-like,
multikringle glycoprotein in Lp(a). We employed a mutational analysis
to localize the lysine-binding domains within human apo(a). Recombinant
apo(a) (r-apo(a)) with 17 plasminogen kringle IV-like domains, one
plasminogen kringle V-like domain, and a protease domain or mutants
thereof were expressed in the human hepatocarcinoma cell line HepG2.
The lysine binding of plasma Lp(a) and r-apo(a) in the culture
supernatants of transfected HepG2 cells was analyzed by
lysine-Sepharose affinity chromatography. Wild type recombinant Lp(a)
(r-Lp(a)) revealed lysine binding in the range observed for human
plasma Lp(a). A single accessible lysine binding site in Lp(a) is
indicated by a complete loss of lysine binding observed for r-Lp(a)
species that contain either a truncated r-apo(a) lacking kringle IV-37,
kringle V, and the protease or a point-mutated r-apo(a) with a Trp-4174
Arg substitution in the putative lysine-binding pocket of
kringle IV-37. Evidence is also presented for additional lysine-binding
sites within kringles 32-36 of apo(a) that are masked in Lp(a) as
indicated by an increased lysine binding for the point mutant (Cys-4057
Ser), which is unable to assemble into particles. An important
role of these lysine-binding site(s) for Lp(a) assembly is suggested by
a decreased assembly efficiency for deletion mutants lacking either
kringle 32 or kringles 32-35.

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Copyright © 1995 by the American Society for Biochemistry and Molecular Biology.
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