COMPARISON OF LIGAND-BINDING SITES OF MODELED APO[A] KRINGLE-LIKE SEQUENCES IN HUMAN LIPOPROTEIN[A]

Human lipoprotein[a] contains at least two high-molecular-weight, disu lfide-linked apolipoproteins, apo[a] and apo B-100. Apo[a] is a highly glycosylated, hydrophilic apoprotein that somewhat resembles plasmino gen by containing an extended kringle domain and a carboxyl-terminal s erine protease domain. The apo[a] kringle domain is composed of 11 dis tinct kringle types. Ten of these display high sequence homology to pl asminogen kringle 4 (PGK4). The crystallographic coordinates for PGK4 were used to generate three-dimensional molecular models of the apo[al kringle types, and the lysine-binding region of PGK4 was used to comp are the different potential receptor-ligand and ligand-binding sites c ontained in each different PGK4-like kringle of apo[a]. A receptor-lig and site can be proposed for each kringle type. Potential serine prote ase cleavage sites, containing arginine-threonine and threonine-argini ne, are located on the surface of the kringles. The ligand-binding sit e of one apo[a] kringle model is almost identical to that of PGK4 and may be a lysine-binding site of apo[a]. Four other apo[a] kringle mode ls appear to have structurally similar lysine-binding sites, but with differences that may influence ligand-polypeptide specificity. Five ap o[a] kringle models have ligand-binding sites that probably do not bin d lysine; one of these is the highly repeated kringle in the known apo [a] polymorph.