Interaction of fibrin(ogen) with apolipoprotein(a): further characterization and identification of a novel lysine-dependent apolipoprotein(a)-binding site within the gamma chain 287-411 region.
Interaction of lipoprotein(a) with fibrin associated with atherosclerotic lesions promotes its accumulation in the lesions, thereby contributing to the development of atherothrombosis. Numerous studies revealed that this interaction occurs through the apolipoprotein(a) [apo(a)] component of lipoprotein(a) and COOH-terminal Lys residues generated by partial degradation of fibrin with plasmin (a COOH-Lys-dependent mechanism). At the same time, the mechanism of the interaction of apo(a) with intact fibrin(ogen) remained unclear. Our recent study identified the Lys-independent apo(a)-binding sites within the fibrin(ogen) alphaC domains which contribute to an alternative Lys-independent mechanism. In this study, we performed direct measurements of the interaction between apo(a) and various fibrin(ogen) fragments representing the whole fibrin(ogen) molecule except the alphaC regions. The experiments revealed that the apo(a)-binding site, identified previously within fibrinogen gamma chain residues 207-235 [Klose, R., et al. (2000) J. Biol. Chem. 275, 38206-38212], is a high-affinity site and mainly Lys-independent, suggesting that it should also contribute to the Lys-independent mechanism. The experiments also identified a novel Lys-dependent high-affinity apo(a)-binding site within the sequence of gamma chain residues 287-411. This site may provide interaction of apo(a) with intact fibrin(ogen) through another alternative mechanism, which depends on internal Lys residues. Thus, apo(a) may interact with intact fibrin through the Lys-independent and Lys-dependent mechanisms, while the COOH-Lys-dependent mechanism may prevail in the presence of fibrinolytic activity.
Tsurupa
Galina
G
Center for Vascular and Inflammatory Diseases and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Yakovlev
Sergiy
S
Pechik
Igor
I
Lamanuzzi
Leila B
LB
Anglés-Cano
Eduardo
E
Medved
Leonid
L
D001053:Apolipoproteins / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D001667:Binding, Competitive; D005337:Fibrin / Q000737:chemistry* / Q000493:pharmacokinetics; D005340:Fibrinogen / Q000737:chemistry* / Q000493:pharmacokinetics; D007700:Kinetics; D008239:Lysine; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry; D010447:Peptide Hydrolases; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D001053:Apolipoproteins; D010446:Peptide Fragments; D005337:Fibrin; D005340:Fibrinogen; D010447:Peptide Hydrolases; D008239:Lysine