Alpha 2-macroglobulin receptor mediates binding and cytotoxicity of plant ribosome-inactivating proteins.
It has been proposed that unconjugated type I ribosome-inactivating proteins (RIP) enter cells through passive mechanisms such as fluid-phase pinocytosis. However, some observations, such as the difference in sensitivity to type I RIP among different cell types, and the organ-specific toxicity of type I RIP, indicate a specific mechanism for the entry of these proteins into target cells. The alpha 2-macroglobulin receptor (alpha 2MR) is responsible for the binding and endocytosis of several ligands, including alpha 2-macroglobulin/proteinase complexes, plasminogen-activator-inhibitor complexes, apoE-enriched beta-very low density lipoproteins, and lipoprotein lipase. Here we demonstrate that saporin, a potent type I RIP, binds specifically to purified alpha 2MR and the binding is prevented by some alpha 2MR ligands. Moreover, the occupancy of specific ligand-binding sites on cell surface alpha 2MR decreases the cytotoxicity of saporin. The A chain of ricin, a type II RIP, also interacts with alpha 2MR. This, and the fact that saporin and ricin A chain both interact also with alpha 2-macroglobulin, indicates a general mechanism of complex interactions between RIP and cellular membranes that is mediated by alpha 2-macroglobulin and the alpha 2MR system.
Cavallaro
U
U
Department of Biological and Technological Research, San Raffaele Scientific Institute, Milano, Italy.
Nykjaer
A
A
Nielsen
M
M
Soria
M R
MR
D016923:Cell Death / Q000187:drug effects; D006801:Humans; D000922:Immunotoxins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009699:N-Glycosyl Hydrolases; D010940:Plant Proteins / Q000378:metabolism* / Q000494:pharmacology; D011869:Radioligand Assay; D011971:Receptors, Immunologic / Q000378:metabolism*; D054789:Ribosome Inactivating Proteins, Type 1; D012270:Ribosomes / Q000187:drug effects; D012276:Ricin / Q000378:metabolism* / Q000494:pharmacology; D000076985:Saporins; D014407:Tumor Cells, Cultured; D000511:alpha-Macroglobulins / Q000378:metabolism
D000922:Immunotoxins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010940:Plant Proteins; D011971:Receptors, Immunologic; D054789:Ribosome Inactivating Proteins, Type 1; D000511:alpha-Macroglobulins; D012276:Ricin; D009699:N-Glycosyl Hydrolases; D000076985:Saporins