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A structural assessment of the apo[a] protein of human lipoprotein[a]
J Guevara1, R D Knapp, S Honda
1Department of Medicine, Baylor College of Medicine, Houston, Texas 77030.
Insights
Apolipoprotein[a] (apo[a]) shares structural similarities with plasminogen, suggesting potential positive functions beyond its known atherogenic roles. Analysis reveals apo[a] kringle-type 10 may bind lysine, and proposes an alternative activation site.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Research
Background:
- Lipoprotein[a] (Lp[a]) contains apolipoprotein[a] (apo[a]), a homolog of plasminogen.
- Apo[a] is implicated in atherogenic and thrombogenic processes.
- Understanding apo[a]'s structure may reveal novel functions.
Purpose of the Study:
- To investigate potential positive functions of Lp[a].
- To analyze the primary and secondary structure of apo[a].
- To compare apo[a] with proteins involved in coagulation and fibrinolysis.
Main Methods:
- Sequence comparison of apo[a] with related proteins.
- Structure prediction algorithms for secondary structure analysis.
- Comparative analysis of apo[a] kringle domains with lysine/fibrin-binding kringles.
Main Results:
- Apo[a] possesses kringle and serine protease domains, similar to plasminogen.
- Eleven distinct kringle types were identified in apo[a], with 9 being 114 residues long.
- Apo[a] kringle-type 10 shows high probability for lysine binding; an alternative proteolytic activation site is proposed.
Conclusions:
- Apo[a] structure suggests potential functional roles beyond atherogenesis.
- Structural similarities to plasminogen and identified lysine-binding capabilities warrant further investigation.
- The proposed alternative activation site may be crucial for apo[a] function.
Abstract:
Apolipoprotein[a], the highly glycosylated, hydrophilic apoprotein of lipoprotein[a] (Lp[a]), is generally considered to be a multimeric homologue of plasminogen, and to exhibit atherogenic/thrombogenic properties. The cDNA-inferred amino acid sequence of apo[a] indicates that apo[a], like plasminogen and some zymogens, is composed of a kringle domain and a serine protease domain. To gain insight into possible positive functions of Lp[a], we have examined the apo[a] primary structure by comparing its sequence with those of other proteins involved in coagulation and fibrinolysis, and its secondary structure by using a combination of structure prediction algorithms. The kringle domain encompasses 11 distinct types of repeating units, 9 of which contain 114 residues. These units, called kringles, are similar but not identical to each other or to PGK4. Each apo[a] kringle type was compared with kringles which have been shown to bind lysine and fibrin, and with bovine prothrombin kringle 1. Apo[a] kringles are linked by serine/threonine- and proline-rich stretches similar to regions in immunoglobulins, adhesion molecules, glycoprotein Ib-alpha subunit, and kininogen. In comparing the protease domains of apo[a] and plasmin, apo[a] contains a region between positions 4470 and 4492 where 8 substitutions, 9 deletions, and 1 insertion are apparent. Our analysis suggests that apo[a] kringle-type 10 has a high probability of binding to lysine in the same way as PGK4. In the only human apo[a] polymorph sequenced to date, position 4308 is occupied by serine, whereas the homologous position in plasmin is occupied by arginine and is an important site for proteolytic cleavage and activation. An alternative site for the proteolytic activation of human apo[a] is proposed.