| Abstract
| - Insight into the structural features of humanlipoprotein(a) [Lp(a)] which underlie itsfunctionalimplication in fibrinolysis may be gained from comparative studies ofapo(a). Indeed, cloning of rhesusmonkey apo(a) has shown that a Trp72 → Arg mutation in thelysine-binding site (LBS) of KIV-10 leadsto loss of lysine-binding properties of the rhesus Lp(a) particle.Consequently, comparative studies ofapo(a) sequences in different Old World monkey species shouldfurther our understanding of the molecularrole of Lp(a) in the fibrinolytic process. In contrast toother Old World monkeys, including rhesus monkey,cynomolgus, and baboon, the chimpanzee exhibits an elevated level ofLp(a) and a distinct isoformdistribution as compared to humans [Doucet et al. J. LipidRes. (1994) 35, 263−270]. Clearly then,thechimpanzee is an interesting animal model for study of the structure,function, and potential pathophysiological roles of Lp(a). We have cloned and sequenced theregion of chimpanzee apo(a) cDNA spanningKIV-3 to the stop codon. The global organization of this region issimilar to that of human apo(a) withthe presence of KV, which is absent in rhesus monkey apo(a).Nucleotide sequence comparison indicatesa variation of 1.4% between chimpanzee and man and 5.1% betweenchimpanzee and rhesus monkey.The differences concerned single base changes. An Asp57 →Asn mutation was detected in KIV-10; thisresidue is critical to the LBS of KIV-10 in human apo(a). Toverify that the Asp57 → Asn substitutionwas specific to apo(a), we have also cloned the cDNA-encodingplasminogen, which exhibited an Asp atthe corresponding position in kringle IV. Using an in vitrobinding assay, we have demonstrated thatchimpanzee Lp(a) exhibits poor lysine-specific interaction withboth intact and plasmin-degraded fibrinas compared to its human counterpart. We propose that the Asn57substitution in KIV-10 of chimpanzeeapo(a) is responsible for this property. ChimpanzeeLp(a) therefore represents an appropriate particlewith which to explore the potential effects of Lp(a) on thefibrinolytic system, such as the inhibition ofplasminogen activation or inhibition of t-PA activity.
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