Structural requirements for the binding of modified proteins to the scavenger receptor of macrophages.
Oxidized low density lipoprotein (LDL) and certain chemically modified LDL are recognized by the scavenger receptor of macrophages. All of these modifications involve charge-neutralizing derivatization of lysine amino groups. However, it remains controversial whether recognition of modified LDL by this receptor is due to the modification per se, or to other factors such as a conformational change of apoB. In this study, LDL and other proteins including bovine serum albumin, human high density lipoprotein, and murine IgG were derivatized with oxidation products generated from arachidonic acid by thermal autoxidation. Modified proteins had increased negative charge, and showed a more than 10-fold enhancement of degradation by mouse peritoneal macrophages via the scavenger receptor pathway. Modification was prevented by blocking lysine residues of the proteins by prior reductive methylation. Amino acid analysis revealed dose-dependent modification of lysine residues with no significant effects on any other amino acid. Fab fragments of monoclonal antibodies specific for adducts of oxidation products with lysine prevented the uptake of oxidation product-modified LDL and oxidized LDL by macrophages. Chromatography of oxidation product-modified LDL over Sepharose CL-4B showed that uptake by macrophages did not require LDL aggregation. These results suggest that a relatively simple domain consisting of a cluster of suitably derivatized lysine residues is sufficient for recognition by the scavenger receptor of macrophages.
Department of Medicine, University of British Columbia, Vancouver, Canada.
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Steinbrecher
D001055:Apolipoproteins B / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D007074:Immunoglobulin G / Q000737:chemistry / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D010084:Oxidation-Reduction; D011485:Protein Binding; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000378:metabolism
D001055:Apolipoproteins B; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D008077:Lipoproteins, LDL; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D012709:Serum Albumin; D012710:Serum Albumin, Bovine; D008239:Lysine