https://scholars.lib.ntu.edu.tw/handle/123456789/454006
標題: | Structural basis of antizyme-mediated regulation of polyamine homeostasis | 作者: | 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. SHIOU-RU TZENG Hung H.-C. NEI-LI CHAN |
公開日期: | 2015 | 出版社: | National Academy of Sciences | 卷: | 112 | 期: | 36 | 起(迄)頁: | 11229-11234 | 來源出版物: | Proceedings of the National Academy of Sciences of the United States of America | 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 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-in-duced 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. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84941309133&doi=10.1073%2fpnas.1508187112&partnerID=40&md5=c3baecedf556ca8d3e21dbf74afee3f6 https://scholars.lib.ntu.edu.tw/handle/123456789/454006 |
ISSN: | 0027-8424 | DOI: | 10.1073/pnas.1508187112 | SDG/關鍵字: | antizyme; antizyme isoform 1; heterodimer; homodimer; ornithine decarboxylase; polyamine; proteasome; ubiquitin; unclassified drug; antizyme; ATP dependent 26S protease; AZIN1 protein, human; carrier protein; enzyme inhibitor; polyamine; protein; protein binding; Article; binding competition; carboxy terminal sequence; crystal structure; dimerization; enzyme activity; enzyme binding; enzyme degradation; enzyme inhibition; enzyme substrate; functional assessment; homeostasis and regulation; molecular dynamics; molecular recognition; polyamine metabolism; polyamine synthesis; priority journal; structure analysis; surface property; amino acid sequence; biocatalysis; chemistry; homeostasis; human; kinetics; metabolism; molecular genetics; molecular model; protein conformation; protein degradation; protein multimerization; protein secondary structure; protein tertiary structure; sequence homology; X ray crystallography; Amino Acid Sequence; Biocatalysis; Carrier Proteins; Crystallography, X-Ray; Enzyme Inhibitors; Homeostasis; Humans; Kinetics; Models, Molecular; Molecular Sequence Data; Ornithine Decarboxylase; Polyamines; Proteasome Endopeptidase Complex; Protein Binding; Protein Conformation; Protein Multimerization; Protein Structure, Secondary; Protein Structure, Tertiary; Proteins; Proteolysis; Sequence Homology, Amino Acid |
顯示於: | 生物化學暨分子生物學科研究所 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。