ArticleProceedings of the National Academy of Sciences of the United States of America2015
Structural basis of antizyme-mediated regulation of polyamine homeostasis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 75 citations in OpenAlex.
- Proteasomal surveillance of exposed cysteines.bioRxiv : the preprint server for biology · 2026Article
- Molecular basis of ubiquitin-independent recognition and degradation of ODC/Antizyme by the 26S proteasome.bioRxiv : the preprint server for biology · 2026Article
- Pathophysiology-driven use of natural products in irritable bowel syndrome: a review.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- Article
- Article
- Polyamines as Gatekeepers of Virus Replication and Central Nervous System Homeostasis.Pathogens (Basel, Switzerland) · 2026Review
- Metabolic syndrome promotes endometrial cancer by Oleic acid-mediated polyamine accumulation.Nature communications · 2025Article
- Polyamine homeostasisbioRxiv : the preprint server for biology · 2025Article
- Urea cycle dysregulation: a new frontier in cancer metabolism and immune evasion.Cell communication and signaling : CCS · 2025Review
- Structure simulation-based comparison of active site variations in fungal ornithine decarboxylases.Communicative & integrative biology · 2025Article
- Protein degradation of antizyme depends on the N-terminal degrons.Protein science : a publication of the Protein Society · 2024Article
- Nc-RNA-mediated low expression of AZIN1 correlated with unfavorable prognosis in kidney renal clear cell carcinoma.Cancer medicine · 2024Article
- Bachmann-Bupp syndrome and treatment.Developmental medicine and child neurology · 2024Review
- Antizyme inhibitor family: biological and translational research implications.Cell communication and signaling : CCS · 2024Review
- EPLIN-β is a novel substrate of ornithine decarboxylase antizyme 1 and mediates cellular migration.Journal of cell science · 2023Article
- Article
- Concomitant protein pathogenesis in Parkinson's disease and perspective mechanisms.Frontiers in aging neuroscience · 2023Review
- Target of Rapamycin Mediated Ornithine Decarboxylase Antizyme Modulate Intracellular Putrescine and Ganoderic Acid Content in Ganoderma lucidum.Microbiology spectrum · 2022Article
- AZIN1 RNA editing alters protein interactions, leading to nuclear translocation and worse outcomes in prostate cancer.Experimental & molecular medicine · 2022Article
- Structure and Enzymatic Activity of an Intellectual Disability-Associated Ornithine Decarboxylase Variant, G84R.ACS omega · 2022Article
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Polyamines are organic polycations essential for cell growth and differentiation; their aberrant accumulation is often associated with diseases, including many types of cancer. To maintain polyamine homeostasis, the catalytic activity and protein abundance of ornithine decarboxylase (ODC), the committed enzyme for polyamine biosynthesis, are reciprocally controlled by the regulatory proteins antizyme isoform 1 (Az1) and antizyme inhibitor (AzIN). Az1 suppresses polyamine production by inhibiting the assembly of the functional ODC homodimer and, most uniquely, by targeting ODC for ubiquitin-independent proteolytic destruction by the 26S proteasome. In contrast, AzIN positively regulates polyamine levels by competing with ODC for Az1 binding. The structural basis of the Az1-mediated regulation of polyamine homeostasis has remained elusive. Here we report crystal structures of human Az1 complexed with either ODC or AzIN. Structural analysis revealed that Az1 sterically blocks ODC homodimerization. Moreover, Az1 binding triggers ODC degradation by inducing the exposure of a cryptic proteasome-interacting surface of ODC, which illustrates how a substrate protein may be primed upon association with Az1 for ubiquitin-independent proteasome recognition. Dynamic and functional analyses further indicated that the Az1-induced binding and degradation of ODC by proteasome can be decoupled, with the intrinsically disordered C-terminal tail fragment of ODC being required only for degradation but not binding. Finally, the AzIN-Az1 structure suggests how AzIN may effectively compete with ODC for Az1 to restore polyamine production. Taken together, our findings offer structural insights into the Az-mediated regulation of polyamine homeostasis and proteasomal degradation.
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