Evidence that the fibrinogen binding domain of Apo(a) is outside the lysine binding site of kringle IV-10: a study involving naturally occurring lysine binding defective lipoprotein(a) phenotypes.
It is now established that the lysine binding site (LBS) of apo(a) kringle IV-10, and particularly Trp72, plays a dominant role in the binding of lipoprotein(a) [Lp(a)] to lysine. To determine the role of the LBS in the binding of Lp(a) to fibrinogen, we examined the binding to plasmin-modified (PM) fibrinogen of human and rhesus monkey Lp(a) species classified as either Lys' or Lys- based on their capacity to bind lysine Sepharose and to have Trp or Arg, respectively, in position 72 of the LBS of kringle IV-10. We also examined the free apo(a)s obtained by subjecting their corresponding parent Lp(a)s to a mild reductive procedure developed in our laboratory. Our results show that both Lyst and Lys- Lp(a)s and their derived apo(a)s, bound to PM-fibrinogen with similar affinities (Kds: 33-100 nM), whereas the B(max) values were threefold higher for apo(a)s. Both the lysine analog epsilon-aminocaproic acid and L-proline inhibited the binding of Lp(a) and apo(a) to PM fibrinogen. We conclude that the LBS of kringle IV-10 is not involved in this process and that apo(a) binds to PM-fibrinogen via a lysine-proline-sensitive domain located outside the LBS and largely masked by the interaction of apo(a) with apoB100. The significant difference in the PM fibrinogen binding capacity also suggests that apo(a) may have a comparatively higher athero-thrombogenic potential than parent Lp(a).
Klezovitch
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Department of Medicine, University of Chicago, Illinois 60637, USA. oklezovi@medicine.bsd.uchicago.edu
Edelstein
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Scanu
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D000328:Adult; D000368:Aged; D015119:Aminocaproic Acid / Q000494:pharmacology; D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism*; D053241:Apoprotein(a); D001665:Binding Sites; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D006801:Humans; D018082:Kringles; D017270:Lipoprotein(a) / Q000235:genetics / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D008875:Middle Aged; D010958:Plasminogen / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012685:Sepharose / Q000031:analogs & derivatives / Q000378:metabolism
D001053:Apolipoproteins; D005338:Fibrin Fibrinogen Degradation Products; D017270:Lipoprotein(a); C036129:fibrinogen fragment Y; C030675:lysine-sepharose; D010958:Plasminogen; D012685:Sepharose; D053241:Apoprotein(a); D015119:Aminocaproic Acid