Degradation of antizyme inhibitor, an ornithine decarboxylase homologous protein, is ubiquitin-dependent and is inhibited by antizyme.
Ornithine decarboxylase (ODC) is the most notable example of a protein degraded by the 26 S proteasome without ubiquitination. Instead, ODC is targeted to degradation by direct binding to a polyamine-induced protein termed antizyme (Az). Antizyme inhibitor (AzI) is an ODC-related protein that does not retain enzymatic activity yet binds Az with higher affinity than ODC. We show here that like ODC, AzI is also a short-lived protein that undergoes proteasomal degradation. However, in contrast to ODC degradation, the degradation of AzI is ubiquitin-dependent and does not require interaction with Az. Moreover, Az binding actually stabilizes AzI by inhibiting its ubiquitination. Substituting the C terminus of AzI with that of ODC, which together with Az constitutes the complete degradation signal of ODC, does not subvert AzI degradation from the ubiquitin-dependent mode to the Az-dependent mode, suggesting dominance of the ubiquitination signal. Our results suggest opposing roles of Az in regulating the degradation of AzI and ODC.
Bercovich
Zippi
Z
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel.
Kahana
Chaim
C
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D004795:Enzyme Stability; D015870:Gene Expression; D006801:Humans; D007668:Kidney; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016296:Mutagenesis; D041681:NIH 3T3 Cells; D009955:Ornithine Decarboxylase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D011994:Recombinant Proteins; D017385:Sequence Homology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism / Q000494:pharmacology*
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011506:Proteins; D011994:Recombinant Proteins; D025801:Ubiquitin; C031017:ornithine decarboxylase antizyme; C039317:ornithine decarboxylase antizyme inhibitor; D009955:Ornithine Decarboxylase