Receptor-associated protein binding blocks ubiquitinylation of the low density lipoprotein receptor-related protein.
The low density lipoprotein receptor-related protein (LRP) consists of two subunits, M(r) approximately 515,000 and 85,000. LRP is a receptor for activated alpha2-macrogobulin (alpha2M*), Pseudomonas exotoxin A, and many other proteins. We now report that ubiquitinylation of the LRP heavy chain occurred when either Pseudomonas exotoxin A or alpha2M* bound to LRP on macrophages. Ubiquitinylation was dose-dependent and maximal about 30 min after ligation of the receptor. Addition of the proteosome inhibitor MG-132 sustained the level of ubiquitin-LRP for longer time intervals in macrophages treated with either alpha2M* or Pseudomonas exotoxin A. By contrast, when receptor associated protein (RAP) bound to LRP, ubiquitinylation did not occur. While RAP is not found in the extracellular environment it binds to LRP and is believed to function as an intracellular chaperone. The presence of RAP within the cell may, therefore, contribute to the recycling of intact LRP which has ligated and internalized its ligands.
Misra
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UK
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Pizzo
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SV
D036002:ADP Ribose Transferases; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D001427:Bacterial Toxins / Q000378:metabolism; D005098:Exotoxins / Q000378:metabolism; D026563:LDL-Receptor Related Protein-Associated Protein / Q000494:pharmacology*; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D008024:Ligands; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D014452:Ubiquitins / Q000378:metabolism*; D037521:Virulence Factors; D000511:alpha-Macroglobulins / Q000378:metabolism; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D005098:Exotoxins; D026563:LDL-Receptor Related Protein-Associated Protein; D026502:LDL-Receptor Related Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; D014452:Ubiquitins; D037521:Virulence Factors; D000511:alpha-Macroglobulins; D000097668:Pseudomonas aeruginosa Exotoxin A; C111749:pseudomonas exoprotein A protein, Pseudomonas aeruginosa