The cytoplasmic domain of the low density lipoprotein (LDL) receptor-related protein, but not that of the LDL receptor, triggers phagocytosis.
The macrophage LDL receptor and LDL receptor-related protein (LRP, CD91) mediate the phagocytic-like uptake of atherogenic lipoproteins and apoptotic cells, yet the structural basis of their phagocytic functions is not known. To address this issue, we transfected macrophages with chimeric proteins containing the cytoplasmic tails and transmembrane regions of the LDL receptor or LRP and the ectodomain of CD2, which can bind non-opsonized sheep red blood cells (SRBCs). Macrophages expressing receptors containing the LDL receptor domains were able to bind but not internalize SRBCs. In contrast, macrophages expressing receptors containing the cytoplasmic tail of LRP were able to bind and internalize SRBCs. Chimeras in which the LRP cytoplasmic tail was mutated in two di-leucine motifs and a tyrosine in an NPXYXXL motif were able to endocytose anti-CD2 antibody and bind SRBCs, but SRBC phagocytosis was decreased by 70%. Thus, the phagocytic-like functions of LRP, but not those of the LDL receptor, can be explained by the ability of the LRP cytoplasmic tail to trigger phagocytosis. These findings have important implications for atherogenesis and apoptotic cell clearance and for a fundamental cell biological understanding of how the LDL receptor and LRP function in internalization processes.
Patel
Mintoo
M
Department of Medicine, Columbia University, New York, New York 10032, USA.
Morrow
John
J
Maxfield
Frederick R
FR
Strickland
Dudley K
DK
Greenberg
Steven
S
Tabas
Ira
I
D000818:Animals; D018801:CD2 Antigens / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D003593:Cytoplasm / Q000737:chemistry; D004705:Endocytosis; D004912:Erythrocytes; D015870:Gene Expression; D006801:Humans; D007457:Iodine Radioisotopes; D007930:Leucine; D008077:Lipoproteins, LDL / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D010587:Phagocytosis; D021382:Protein Sorting Signals / Q000502:physiology; D011973:Receptors, LDL / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D012756:Sheep / Q000097:blood; D013329:Structure-Activity Relationship; D014162:Transfection; D014443:Tyrosine
D018801:CD2 Antigens; D007457:Iodine Radioisotopes; D008077:Lipoproteins, LDL; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010446:Peptide Fragments; D021382:Protein Sorting Signals; D011973:Receptors, LDL; D011993:Recombinant Fusion Proteins; D014443:Tyrosine; D007930:Leucine