Immunological Approach to Study the Structure of Oxidized Low Density Lipoproteins

Abstract

Human low density lipoproteins (LDL), the major carriers of cholesterol in the bloodstream, plays the major role in supplying cells of tissues and organs with cholesterol. It is derived from the metabolism of the triglyceride-rich very low density lipoproteins (VLDL). Pathologic and epidemiologic studies have implicated that higher concentration of LDL in circulation is correlated with the development of atherosclerosis. Apolipoprotein (apo) B-100 serves as the ligand for the LDL receptor on cell surfaces. Thus, apoB-100 occupies a crucial position in the metabolic pathway of cholesterol and LDL. The complete primary structure of apoB-100 has been determined from its cDNA sequence (Chen et al., 1986; Knott,et al, 1986) and from its proteolytic peptide sequence information (Yang, et. al, 1986). ApoB-100 consists of 4536 amino acid residues with a calculated molecular mass of 513 kDa. Based on the differential trypsin releasibility of apoB-100 in LDL, apoB can be divided into 5 domains. Domain 1 contains 14 of the 25 cysteine (Cys) residues in apoB. Sixteen of the 25 Cys residues (which are numbered from 1 to 25 from the amino end to the carboxy end in apoB-100) exist in disulfide form. All 14 Cys residues in domain 1 are linked in disulfide form, and all except Cys 1-Cys3 and Cys2-Cys4 are linked to neighboring Cys. Domain 4 contains 7 of the 16 N-glycosylated carbohydrates (Yang et al., 1989). Based on the published structural information (Yang et al., 1990), we proposed that the structure of apoB-100 in LDL is likely to be an elongated form that wraps around the LDL molecule as shown in Fig. 1 (Yang et al., 1992). The process of atherogenesis is believed to involve transformation of macrophages to lipid-laden foam cells.