Baboon lipoprotein(a) binds very weakly to lysine-agarose and fibrin despite the presence of a strong lysine-binding site in apolipoprotein(a) kringle IV type 10.
Human apolipoprotein(a) kringle IV type 10 [apo(a) KIV(10)] contains a strong lysine-binding site (LBS) that mediates the interaction of Lp(a) with biological substrates such as fibrin. Mutations in the KIV(10) LBS have been reported in both the rhesus monkey and chimpanzee, and have been proposed to explain the lack of ability of the corresponding Lp(a) species to bind to lysine and fibrin. To further the comparative analyses with other primate species, we sequenced a segment of baboon liver apo(a) cDNA spanning KIV(9) through the protease domain. Like rhesus monkey apo(a), baboon apo(a) lacks a kringle V (KV)-like domain. Interestingly, we found that the baboon apo(a) KIV(10) sequence contains all of the canonical LBS residues. We sequenced the apo(a) KIV(10) sequence from an additional 10 unrelated baboons; 17 of 20 alleles encoded Trp at position 70, whereas only two alleles encoded Arg at this position and thus a defective LBS. Despite the apparent presence of a functional KIV(10) LBS in most of the baboons, none of the Lp(a) in the plasma of the corresponding baboons bound specifically to lysine-Sepharose (agarose) even upon partial purification. Moreover, baboon Lp(a) bound very poorly to plasmin-modified fibrinogen. Expression of baboon and human KIV(10) in bacteria allowed us to verify that these domains bind comparably to lysine and lysine analogues. We conclude that presentation of KIV(10) in the context of apo(a) lacking KV may interfere with the ability of KIV(10) to bind to substrates such as fibrin; this paradigm may also be present in other non-human primates.
Belczewski
Andrea R
AR
Department of Biochemistry, Queen's University, Kingston, Ontario, Canada K7L 3N6.
Ho
Janet
J
Taylor
Fletcher B
FB
Boffa
Michael B
MB
Jia
Zongchao
Z
Koschinsky
Marlys L
ML
D000595:Amino Acid Sequence; D000818:Animals; D001053:Apolipoproteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D053241:Apoprotein(a); D001120:Arginine / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D005337:Fibrin / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D018082:Kringles / Q000235:genetics; D017270:Lipoprotein(a) / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D008099:Liver / Q000737:chemistry; D008239:Lysine / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010215:Papio; D011110:Polymorphism, Genetic; D011485:Protein Binding / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D012685:Sepharose / Q000378:metabolism*; D014364:Tryptophan / Q000235:genetics
D001053:Apolipoproteins; D017270:Lipoprotein(a); D011994:Recombinant Proteins; D014364:Tryptophan; D005337:Fibrin; D012685:Sepharose; D001120:Arginine; D053241:Apoprotein(a); D008239:Lysine