Structural basis of antizyme-mediated regulation of polyamine homeostasis

摘要: 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 protein abundance ornithine decarboxylase (ODC), committed enzyme biosynthesis, reciprocally controlled by regulatory proteins antizyme isoform 1 (Az1) inhibitor (AzIN). Az1 suppresses production inhibiting assembly functional ODC homodimer and, most uniquely, targeting ubiquitin-independent proteolytic destruction 26S proteasome. In contrast, AzIN positively regulates levels competing binding. The structural basis Az1-mediated regulation homeostasis has remained elusive. Here we report crystal structures human complexed either or AzIN. Structural analysis revealed that sterically blocks homodimerization. Moreover, binding triggers degradation inducing exposure a cryptic proteasome-interacting surface ODC, which illustrates how substrate may be primed upon association proteasome recognition. Dynamic analyses further indicated Az1-induced can decoupled, intrinsically disordered C-terminal tail fragment being required only but not Finally, AzIN-Az1 structure suggests effectively compete to restore production. Taken together, our findings offer insights into Az-mediated proteasomal degradation.