4ZGZ

STRUCTURE OF HUMAN ANTIZYME INHIBITOR IN COMPLEX WITH A C-TERMINAL FRAGMENT OF ANTIZYME

Summary for 4ZGZ

• Entry DOI: 10.2210/pdb4zgz/pdb
• Related: 1ZO0 3BTN 4QCG
• Descriptor: Antizyme inhibitor 1, Ornithine decarboxylase antizyme 1 (2 entities in total)
• Functional Keywords: tim barrel domain, beta-sheet domain, inhibition, antizyme, plasma, protein binding
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : O14977
• Total number of polymer chains: 4
• Total formula weight: 126499.04

Authors

Chen, S.F.,Wu, H.Y.,Chan, N.L. (deposition date: 2015-04-24, release date: 2015-09-02, Last modification date: 2023-11-29)

Primary citation

Wu, H.Y.,Chen, S.F.,Hsieh, J.Y.,Chou, F.,Wang, Y.H.,Lin, W.T.,Lee, P.Y.,Yu, Y.J.,Lin, L.Y.,Lin, T.S.,Lin, C.L.,Liu, G.Y.,Tzeng, S.R.,Hung, H.C.,Chan, N.L.
Structural basis of antizyme-mediated regulation of polyamine homeostasis
Proc.Natl.Acad.Sci.USA, 112:11229-11234, 2015

PubMed 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.

PubMed: 26305948
DOI: 10.1073/pnas.1508187112

Experimental method

X-RAY DIFFRACTION (5.81 Å)