Apo(a) is the main constituent of lipoprotein(a) (Lp(a)). It has serine proteinase activity and is able of autoproteolysis. Inhibits tissue-type plasminogen activator 1. Lp(a) may be a ligand for megalin/Gp 330.
The plasma concentration of human lipoprotein(a) [Lp(a)] is correlated with the risk of heart disease. A distinct feature of the Lp(a) particle is the apolipoprotein (a) [apo(a)], which is associated with apoB-100, the main protein component of low-density lipoprotein. We now report that apo(a), which has extensive homology to plasminogen, binds to immobilized fibronectin. The binding of Lp(a) was localized to the C-terminal heparin-binding domain of fibronectin. Incubation of Lp(a) with fibronectin resulted in fragmentation of fibronectin. The cleavage pattern, as visualized by gel electrophoresis and immunoblotting, was reproducibly obtained with Lp(a) purified from five different individuals and was distinct from that obtained upon proteolysis of fibronectin by plasmin or kallikrein. The use of synthetic peptide substrates demonstrated that the amino acid specificity for Lp(a) was arginine rather than lysine. The proteolytic activity of Lp(a) was localized to apo(a) and experiments with inhibitors indicated that the proteolytic activity was of serine proteinase-type.
Lipoprotein(a) [Lp(a)], which has been shown to interact with fibrin(ogen) and other components of the blood clotting cascade, is a major independent risk factor for atherothrombotic disease in humans. The physiological function(s) of Lp(a), as well as the precise mechanism(s) by which high plasma levels of Lp(a) increase risk are unknown. Identification of further potential apo(a)-protein ligands may be crucial to illuminate apo(a)'s function(s) and pathophysiological properties. We used the repetitive apo(a) kringle IV type 2, which is variable in number in apo(a), to screen a human liver cDNA library by the yeast two-hybrid interaction trap system. Among 11 positive clones that emerged from the screen, eight clones were identified as beta-2 glycoprotein I and one as fibronectin. Coimmunoprecipitation experiments confirmed that beta-2 glycoprotein I and apo(a)/Lp(a) interact in human plasma and in cell culture supernatants of COS-1 cells, which ectopically expressed apo(a). The apo(a)-beta2-glycoprotein I interaction indicates new potential roles for Lp(a) in fibrinolysis and autoimmunity.
A HIGH concentration of serum lipoprotein(a) is a risk factor for atherosclerosis. Lipoprotein(a) consists of low-density lipoprotein with the additional protein component, apolipoprotein(a), a homologue of plasminogen. Lipoprotein(a) and apolipoprotein(a) enhance proliferation of human vascular smooth muscle cells (hVSMCs) in culture by inhibiting activation of plasminogen to plasmin, thus blocking the proteolytic activation of transforming growth factor-beta (TGF-beta), an autocrine inhibitor of hVSMC proliferation. The hypothesis that this pathway is a key step in atherogenesis is tested on transgenic mice expressing the human apolipoprotein(a) gene. We show here that the activation of TGF-beta is inhibited in the aortic wall and serum of mice expressing apolipoprotein(a), as a consequence of apolipoprotein(a) inhibition of plasminogen activation. These effects are closely correlated with VSMC activation.
Interacting selectively and non-covalently with a fibronectin, a group of related adhesive glycoproteins of high molecular weight found on the surface of animal cells, connective tissue matrices, and in extracellular fluids.
Evidence
1:
Inferred from Physical InteractionBHF-UCL
The plasma concentration of human lipoprotein(a) [Lp(a)] is correlated with the risk of heart disease. A distinct feature of the Lp(a) particle is the apolipoprotein (a) [apo(a)], which is associated with apoB-100, the main protein component of low-density lipoprotein. We now report that apo(a), which has extensive homology to plasminogen, binds to immobilized fibronectin. The binding of Lp(a) was localized to the C-terminal heparin-binding domain of fibronectin. Incubation of Lp(a) with fibronectin resulted in fragmentation of fibronectin. The cleavage pattern, as visualized by gel electrophoresis and immunoblotting, was reproducibly obtained with Lp(a) purified from five different individuals and was distinct from that obtained upon proteolysis of fibronectin by plasmin or kallikrein. The use of synthetic peptide substrates demonstrated that the amino acid specificity for Lp(a) was arginine rather than lysine. The proteolytic activity of Lp(a) was localized to apo(a) and experiments with inhibitors indicated that the proteolytic activity was of serine proteinase-type.
Interacting selectively and non-covalently with heparin, any member of a group of glycosaminoglycans found mainly as an intracellular component of mast cells and which consist predominantly of alternating alpha-(1->4)-linked D-galactose and N-acetyl-D-glucosamine-6-sulfate residues.
The plasma concentration of human lipoprotein(a) [Lp(a)] is correlated with the risk of heart disease. A distinct feature of the Lp(a) particle is the apolipoprotein (a) [apo(a)], which is associated with apoB-100, the main protein component of low-density lipoprotein. We now report that apo(a), which has extensive homology to plasminogen, binds to immobilized fibronectin. The binding of Lp(a) was localized to the C-terminal heparin-binding domain of fibronectin. Incubation of Lp(a) with fibronectin resulted in fragmentation of fibronectin. The cleavage pattern, as visualized by gel electrophoresis and immunoblotting, was reproducibly obtained with Lp(a) purified from five different individuals and was distinct from that obtained upon proteolysis of fibronectin by plasmin or kallikrein. The use of synthetic peptide substrates demonstrated that the amino acid specificity for Lp(a) was arginine rather than lysine. The proteolytic activity of Lp(a) was localized to apo(a) and experiments with inhibitors indicated that the proteolytic activity was of serine proteinase-type.
Catalysis of the hydrolysis of internal, alpha-peptide bonds in a polypeptide chain by a catalytic mechanism that involves a catalytic triad consisting of a serine nucleophile that is activated by a proton relay involving an acidic residue (e.g. aspartate or glutamate) and a basic residue (usually histidine).
The plasma concentration of human lipoprotein(a) [Lp(a)] is correlated with the risk of heart disease. A distinct feature of the Lp(a) particle is the apolipoprotein (a) [apo(a)], which is associated with apoB-100, the main protein component of low-density lipoprotein. We now report that apo(a), which has extensive homology to plasminogen, binds to immobilized fibronectin. The binding of Lp(a) was localized to the C-terminal heparin-binding domain of fibronectin. Incubation of Lp(a) with fibronectin resulted in fragmentation of fibronectin. The cleavage pattern, as visualized by gel electrophoresis and immunoblotting, was reproducibly obtained with Lp(a) purified from five different individuals and was distinct from that obtained upon proteolysis of fibronectin by plasmin or kallikrein. The use of synthetic peptide substrates demonstrated that the amino acid specificity for Lp(a) was arginine rather than lysine. The proteolytic activity of Lp(a) was localized to apo(a) and experiments with inhibitors indicated that the proteolytic activity was of serine proteinase-type.
A HIGH concentration of serum lipoprotein(a) is a risk factor for atherosclerosis. Lipoprotein(a) consists of low-density lipoprotein with the additional protein component, apolipoprotein(a), a homologue of plasminogen. Lipoprotein(a) and apolipoprotein(a) enhance proliferation of human vascular smooth muscle cells (hVSMCs) in culture by inhibiting activation of plasminogen to plasmin, thus blocking the proteolytic activation of transforming growth factor-beta (TGF-beta), an autocrine inhibitor of hVSMC proliferation. The hypothesis that this pathway is a key step in atherogenesis is tested on transgenic mice expressing the human apolipoprotein(a) gene. We show here that the activation of TGF-beta is inhibited in the aortic wall and serum of mice expressing apolipoprotein(a), as a consequence of apolipoprotein(a) inhibition of plasminogen activation. These effects are closely correlated with VSMC activation.
The directed movement of lipids into, out of or within a cell, or between cells, by means of some agent such as a transporter or pore. Lipids are compounds soluble in an organic solvent but not, or sparingly, in an aqueous solvent.
A HIGH concentration of serum lipoprotein(a) is a risk factor for atherosclerosis. Lipoprotein(a) consists of low-density lipoprotein with the additional protein component, apolipoprotein(a), a homologue of plasminogen. Lipoprotein(a) and apolipoprotein(a) enhance proliferation of human vascular smooth muscle cells (hVSMCs) in culture by inhibiting activation of plasminogen to plasmin, thus blocking the proteolytic activation of transforming growth factor-beta (TGF-beta), an autocrine inhibitor of hVSMC proliferation. The hypothesis that this pathway is a key step in atherogenesis is tested on transgenic mice expressing the human apolipoprotein(a) gene. We show here that the activation of TGF-beta is inhibited in the aortic wall and serum of mice expressing apolipoprotein(a), as a consequence of apolipoprotein(a) inhibition of plasminogen activation. These effects are closely correlated with VSMC activation.
Protein involved in the transport of lipids, a diverse class of compounds which are insoluble in water but soluble in organic solvents. They include fats, oils, triacylglycerols, fatty acids, glycolipids, phospholipids and steroids.
Protein involved in the transport of a molecule (metabolite, protein, etc), a ion or an electron across cell membranes, inside the cell or in a tissue fluid.
Enzyme which catalyzes hydrolysis reaction, i.e. the addition of the hydrogen and hydroxyl ions of water to a molecule with its consequent splitting into two or more simpler molecules.
Proteolytic enzyme with a serine residue (Ser) in its active site. The reactivity of the serine residue is ensured by the vicinity of a histidine and an aspartate residue (catalytic triad), all three residues are required for the charge relay system to take place.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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