Abstract
BackgroundAtherosclerosis (AS) is a common cardiovascular disease. Transformation of macrophages to form foam cells by internalizing modified low density-lipoprotein (LDL) via scavenger receptor (SR) is a key pathogenic process in the onset of AS. It has been demonstrated that SR-PSOX functions as either a scavenger receptor for uptake of atherogenic lipoproteins and bacteria or a membrane-anchored chemokine for adhesion of macrophages and T-cells to the endothelium. Therefore, SR-PSOX plays an important role in the development of AS. In this study the key basic amino acids in the chemokine domain of SR-PSOX have been identified for its functions.ResultsA cell model to study the functions of SR-PSOX was successfully established. Based on the cell model, a series of mutants of human SR-PSOX were constructed by replacing the single basic amino acid residue in the non-conservative region of the chemokine domain (arginine 62, arginine 78, histidine 80, arginine 82, histidine 85, lysine 105, lysine 119, histidine 123) with alanine (designated as R62A, R78A, H80A, R82A, H85A, K105A, K119A and H123A, respectively). Functional studies showed that the mutants with H80A, H85A, and K105A significantly increased the activities of oxLDL uptake and bacterial phagocytosis compared with the wild-type SR-PSOX. In addition, we have also found that mutagenesis of either of those amino acids strongly reduced the adhesive activity of SR-PSOX by using a highly non-overlapping set of basic amino acid residues.ConclusionOur study demonstrates that basic amino acid residues in the non-conservative region of the chemokine domain of SR-PSOX are critical for its functions. Mutation of H80, H85, and K105 is responsible for increasing SR-PSOX binding with oxLDL and bacteria. All the basic amino acids in this region are important in the cells adhesion via SR-PSOX. These findings suggest that mutagenesis of the basic amino acids in the chemokine domain of SR-PSOX may contribute to atherogenesis.
Highlights
Atherosclerosis (AS) is a common cardiovascular disease
We demonstrate that the basic amino acids in the nonconservative region of the chemokine domain play a central role in the uptake of oxLDL, phagocytosis of bacteria and adhesive activity of scavenger receptor (SR)-PSOX
The results reveal that non-conservative basic amino acids in the chemokine domain are critical for the functions of scavenger receptor for phosphatidylserine and oxidized lipoprotein (SR-PSOX)
Summary
Transformation of macrophages to form foam cells by internalizing modified low density-lipoprotein (LDL) via scavenger receptor (SR) is a key pathogenic process in the onset of AS. It has been demonstrated that SR-PSOX functions as either a scavenger receptor for uptake of atherogenic lipoproteins and bacteria or a membrane-anchored chemokine for adhesion of macrophages and T-cells to the endothelium. In this study the key basic amino acids in the chemokine domain of SR-PSOX have been identified for its functions. Further studies show that the protein of SR-PSOX exists in either a membrane-bound or a soluble form. SR-PSOX in the membrane-bound form is a type I transmembrane glycoprotein with 254-amino acids, consisting of CXC chemokine, mucin stalk, transmembrane and cytoplasmic domains [15]. The relevance of the serum SR-PSOX and CAD needs to be further investigated
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