Comparison of ligand-binding sites of modeled apo[a] kringle-like sequences in human lipoprotein[a].

Abstract

Human lipoprotein [a] contains at least two high-molecular-weight, disulfide-linked apolipoproteins, apo [a] and apo B-100. Apo[a] is a highly glycosylated, hydrophilic apoprotein that somewhat resembles plasminogen by containing an extended kringle domain and a carboxyl-terminal serine protease domain. The apo [a] kringle domain is composed of 11 distinct kringle types. Ten of these display high sequence homology to plasminogen kringle 4 (PGK4). The crystallographic coordinates for PGK4 were used to generate three-dimensional molecular models of the apo[a] kringle types, and the lysine-binding region of PGK4 was used to compare the different potential receptor-ligand and ligand-binding sites contained in each different PGK4-like kringle of apo [a]. A receptor-ligand site can be proposed for each kringle type. Potential serine protease cleavage sites, containing arginine-threonine and threonine-arginine, are located on the surface of the kringles.

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

“…1) (4,23). However, the LBSs in KIV 5 -KIV 8 have been demonstrated to be of a lower affinity than the one in KIV 10 , due to some conservative amino acid substitutions (24,25).…”

Lipoprotein(a) vascular accumulation in mice. In vivo analysis of the role of lysine binding sites using recombinant adenovirus.

“…1]. Based on several lines of evidence from studies using molecular modeling, mutagenesis and proteolyticallyderived apo(a) fragments, the deletion of NH 2 -terminal kringle domains from apo(a) should not significantly impact properties of mini apo(a) relevant to this study (24)(25)(26)(27)(28). The two putative lysine binding defective apo(a) cDNAs were analogous to mini apo(a) in their construction, containing structural modifications reported to be associated with diminished lysine-Sepharose binding properties (20,22).…”

Identification and Characterization of Novel Lysine-independent Apolipoprotein(a)-binding Sites in Fibrin(ogen) αC-domains

“…Because of these structural similarities, Lp(a) was implicated in the delivery of cholesterol to injured blood vessels (13) and in competition with plasminogen for binding to fibrin and cellular surfaces (14); interaction between Lp(a) and fibrin may play a critical role in both cases. It has been established that both plasminogen and apo(a) contain Lys-binding sites (15,16). It is also known that binding of plasminogen to fibrin via these sites is important for its conversion into an active enzyme, plasmin (17)(18)(19).…”