Mutation of lysine residues in apolipoprotein B-100 causes defective lipoprotein[a] formation
Lipoprotein[a] (Lp[a]) is assembled by a two-step process involving an initial lysine-dependent binding between apolipoprotein B-100 (apoB-100) and apolipoprotein[a] (apo[a]) that facilitates the formation of a disulphide bond between apoB-100Cys4,326 and apo[a]Cys4,057. Previous studies of transgen...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2004-01-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520319210 |
| _version_ | 1828941287624015872 |
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| author | Catherine Y.Y. Liu Ric Broadhurst Santica M. Marcovina Sally P.A. McCormick |
| author_facet | Catherine Y.Y. Liu Ric Broadhurst Santica M. Marcovina Sally P.A. McCormick |
| author_sort | Catherine Y.Y. Liu |
| collection | DOAJ |
| description | Lipoprotein[a] (Lp[a]) is assembled by a two-step process involving an initial lysine-dependent binding between apolipoprotein B-100 (apoB-100) and apolipoprotein[a] (apo[a]) that facilitates the formation of a disulphide bond between apoB-100Cys4,326 and apo[a]Cys4,057. Previous studies of transgenic mice expressing apoB-95 (4,330 amino acids) and apoB-97 (4,397 amino acids) have shown that apoB-100 amino acids 4,330–4,397 are important for the initial binding to apo[a]. Furthermore, a lysine-rich peptide spanning apoB-100 amino acids 4,372–4,392 has recently been shown to bind apo[a] and inhibit Lp[a] assembly in vitro. This suggests that a putative apo[a] binding site exists in the apoB-4,372–4,392 region. The aim of our study was to establish whether the apoB-4,372–4,392 sequence was important for Lp[a] assembly in the context of the full-length apoB-100. Transgenic mice were created that expressed a mutant human apoB-100, apoB-100K4→S4, in which all four lysine residues in the 4,372–4,392 sequence were mutated to serines. The apoB-100K4→S4 mutant showed a reduced capacity to form Lp[a] in vitro compared with wild-type human apoB-100. Double transgenic mice expressing both apoB-100K4→S4 and apo[a] contained significant amounts of free apo[a] in the plasma, indicating a less-efficient assembly of Lp[a] in vivo.Taken together, these results clearly show that the apoB-4,372–4,392 sequence plays a role in Lp[a] assembly. |
| first_indexed | 2024-12-14T03:33:44Z |
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| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-14T03:33:44Z |
| publishDate | 2004-01-01 |
| publisher | Elsevier |
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| series | Journal of Lipid Research |
| spelling | doaj.art-080c5cf7be644712a150db28e007f71f2022-12-21T23:18:40ZengElsevierJournal of Lipid Research0022-22752004-01-014516370Mutation of lysine residues in apolipoprotein B-100 causes defective lipoprotein[a] formationCatherine Y.Y. Liu0Ric Broadhurst1Santica M. Marcovina2Sally P.A. McCormick3Department of Biochemistry, University of Otago, Dunedin, New Zealand; AgResearch Ruakura, Hamilton, New Zealand; Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103Department of Biochemistry, University of Otago, Dunedin, New Zealand; AgResearch Ruakura, Hamilton, New Zealand; Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103Department of Biochemistry, University of Otago, Dunedin, New Zealand; AgResearch Ruakura, Hamilton, New Zealand; Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103Department of Biochemistry, University of Otago, Dunedin, New Zealand; AgResearch Ruakura, Hamilton, New Zealand; Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103Lipoprotein[a] (Lp[a]) is assembled by a two-step process involving an initial lysine-dependent binding between apolipoprotein B-100 (apoB-100) and apolipoprotein[a] (apo[a]) that facilitates the formation of a disulphide bond between apoB-100Cys4,326 and apo[a]Cys4,057. Previous studies of transgenic mice expressing apoB-95 (4,330 amino acids) and apoB-97 (4,397 amino acids) have shown that apoB-100 amino acids 4,330–4,397 are important for the initial binding to apo[a]. Furthermore, a lysine-rich peptide spanning apoB-100 amino acids 4,372–4,392 has recently been shown to bind apo[a] and inhibit Lp[a] assembly in vitro. This suggests that a putative apo[a] binding site exists in the apoB-4,372–4,392 region. The aim of our study was to establish whether the apoB-4,372–4,392 sequence was important for Lp[a] assembly in the context of the full-length apoB-100. Transgenic mice were created that expressed a mutant human apoB-100, apoB-100K4→S4, in which all four lysine residues in the 4,372–4,392 sequence were mutated to serines. The apoB-100K4→S4 mutant showed a reduced capacity to form Lp[a] in vitro compared with wild-type human apoB-100. Double transgenic mice expressing both apoB-100K4→S4 and apo[a] contained significant amounts of free apo[a] in the plasma, indicating a less-efficient assembly of Lp[a] in vivo.Taken together, these results clearly show that the apoB-4,372–4,392 sequence plays a role in Lp[a] assembly.http://www.sciencedirect.com/science/article/pii/S0022227520319210apolipoprotein[a]assemblycoronary heart diseaselysinesite-directed mutagenesistransgenic mice |
| spellingShingle | Catherine Y.Y. Liu Ric Broadhurst Santica M. Marcovina Sally P.A. McCormick Mutation of lysine residues in apolipoprotein B-100 causes defective lipoprotein[a] formation Journal of Lipid Research apolipoprotein[a] assembly coronary heart disease lysine site-directed mutagenesis transgenic mice |
| title | Mutation of lysine residues in apolipoprotein B-100 causes defective lipoprotein[a] formation |
| title_full | Mutation of lysine residues in apolipoprotein B-100 causes defective lipoprotein[a] formation |
| title_fullStr | Mutation of lysine residues in apolipoprotein B-100 causes defective lipoprotein[a] formation |
| title_full_unstemmed | Mutation of lysine residues in apolipoprotein B-100 causes defective lipoprotein[a] formation |
| title_short | Mutation of lysine residues in apolipoprotein B-100 causes defective lipoprotein[a] formation |
| title_sort | mutation of lysine residues in apolipoprotein b 100 causes defective lipoprotein a formation |
| topic | apolipoprotein[a] assembly coronary heart disease lysine site-directed mutagenesis transgenic mice |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520319210 |
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