cDNA Sequence of Human Apolipoprotein(a) Is Homologous to Plasminogen

This 1987 Nature paper is one of the landmark papers in lipoprotein biology: it determined the primary structure of apolipoprotein(a) — the defining protein of Lp(a) — and revealed that it is structurally homologous to plasminogen, the precursor of the fibrinolytic enzyme plasmin.

The apo(a) sequence contained a serine protease domain resembling plasminogen, two types of plasminogen-like kringle domains, and — crucially — 37 copies of the kringle IV type found in plasminogen. This multiplied kringle IV domain explains apo(a)’s size polymorphism: different individuals carry different numbers of kringle IV repeats, producing the enormous variation in apo(a) size and Lp(a) concentration seen in the population. The protein is disulfide-linked to apolipoprotein B-100 in the Lp(a) particle.

The clinical significance of this discovery was recognized immediately and continues to resonate: apo(a)’s homology to plasminogen provides a molecular mechanism for why Lp(a) might impair fibrinolysis — by competing with plasminogen at fibrin binding sites without providing the same proteolytic activity. This explains why elevated Lp(a) is both atherogenic and potentially prothrombotic, and why Lp(a) exists at all in evolutionary terms.

We rate the evidence strong in clinical significance. A foundational molecular biology paper — the structural discovery that made all subsequent mechanistic work on Lp(a) possible and that still informs therapeutic development.