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

Abstract

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.

Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a)

“…The evolution of Lp(a) in apes and monkeys from PLG has occurred concomitantly with losing the lysine binding properties of the KIV 10 LBS. This has occurred through a variety of mechanisms, including loss of KV and/or modifi cations of KIV 10 LBS ( 49,55,56 ). Along with loss of lysine binding, these species also do not have E06 immunoreactivity on Lp(a).…”

“…However, baboon Lp(a), as opposed to apo(a), does not bind to lysine or to plasmin-modifi ed fi brinogen ( 49 ). Interestingly, KV is absent in baboon apo(a) and thus, in baboon Lp(a) the absence of KV appears to prevent access to lysine resides in the KIV 10 LBS due to altered apo(a) confi rmation causing steric hindrance ( 49 ). Even in humans, signifi cant lysine binding heterogeneity of apo(a) exists among different subjects, and part of this heterogeneity may be mediated by noncovalent associations of Lp(a) with other circulating proteins that may mask the KIV 10 LBS ( 50, 51 ).…”

“…In most baboons, an intact LBS on apo(a) is functionally present that is similar to the human apo(a) that binds lysine. However, baboon Lp(a), as opposed to apo(a), does not bind to lysine or to plasmin-modifi ed fi brinogen ( 49 ). Interestingly, KV is absent in baboon apo(a) and thus, in baboon Lp(a) the absence of KV appears to prevent access to lysine resides in the KIV 10 LBS due to altered apo(a) confi rmation causing steric hindrance ( 49 ).…”

Inhibition of plasminogen activation by apo(a): role of carboxyl-terminal lysines and identification of inhibitory domains in apo(a)

“…Critical roles for KIV types 5-9 and KV were identifi ed in inhibiting Glu-to Lys-plasminogen conversion on fi brin ( 34 ). Interestingly, apo(a) from baboons and rhesus monkeys does not contain KV and is not prone to atherosclerosis ( 66,67 ). In the case of baboons, the absence of KV renders the Lp(a) particle incapable of binding to lysine despite the presence of an intact strong LBS in KIV 10 ( 66 ).…”

Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease?

“…With respect to KIV 10 , some species, such as chimpanzees, have a key amino acid substitution that abolishes the LBSs (34). In other species, such as baboon, the LBS is intact (in most individuals), but the lack of KV in this species prevents binding of Lp(a) to lysine-Sepharose, perhaps by promoting a conformation of apo(a) within the Lp(a) particle that masks the KIV 10 LBSs (36). Crucially, human Lp(a) can bind to lysine-Sepharose and other lysine-containing substrates, as it contains both KV and an intact LBS in KIV 10 , and is unique in this respect among the primates examined, except for orangutans (35).…”