TITLE

Structural basis of Ornithine Decarboxylase inactivation and accelerated degradation by polyamine sensor Antizyme1

AUTHOR(S)
Donghui Wu; Hung Yi Kristal Kaan; Xiaoxia Zheng; Xuhua Tang; Yang He; Qianmin Vanessa Tan; Neng Zhang; Haiwei Song
PUB. DATE
October 2015
SOURCE
Scientific Reports;10/9/2015, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Ornithine decarboxylase (ODC) catalyzes the first and rate-limiting step of polyamine biosynthesis in humans. Polyamines are essential for cell proliferation and are implicated in cellular processes, ranging from DNA replication to apoptosis. Excessive accumulation of polyamines has a cytotoxic effect on cells and elevated level of ODC activity is associated with cancer development. To maintain normal cellular proliferation, regulation of polyamine synthesis is imposed by Antizyme1 (AZ1). The expression of AZ1 is induced by a ribosomal frameshifting mechanism in response to increased intracellular polyamines. AZ1 regulates polyamine homeostasis by inactivating ODC activity and enhancing its degradation. Here, we report the structure of human ODC in complex with N-terminally truncated AZ1 (cAZ1). The structure shows cAZ1 binding to ODC, which occludes the binding of a second molecule of ODC to form the active homodimer. Consequently, the substrate binding site is disrupted and ODC is inactivated. Structural comparison shows that the binding of cAZ1 to ODC causes a global conformational change of ODC and renders its C-terminal region flexible, therefore exposing this region for degradation by the 26S proteasome. Our structure provides the molecular basis for the inactivation of ODC by AZ1 and sheds light on how AZ1 promotes its degradation.
ACCESSION #
110327889

 

Related Articles

  • Interaction of Biologically Active Amines with Mitochondria and Their Role in the Mitochondrial-Mediated Pathway of Apoptosis. Toninello, A.; Salvi, M.; Mondovì, B. // Current Medicinal Chemistry;Sep2004, Vol. 11 Issue 17, p2349 

    The natural polyamines spermine, spermidine and putrescine, polycationic molecules at physiological pH, interact with mitochondrial membranes at two specific binding sites exhibiting low affinity and high binding capacity. This binding represents the first step in the electrophoretic mechanism...

  • Glucocorticoids and Polyamine Inhibitors Synergize to Kill Human Leukemic CEM Cells. Miller, Aaron L.; Johnson, Betty H.; Medh, Rheem D.; Townsend, Courtney M.; Thompson, E. Brad // Neoplasia;Jan/Feb2002, Vol. 4 Issue 1, p68 

    Focuses on the ability of polyamine inhibitors to influence glucocorticoid-induced apoptosis in human lymphoblastic leukemic CEM cells. Effect of synthetic glucocorticoid dexamethasone on ornithine decarboxylase activity, mRNA and protein in CEM cells; Extent and onset of apoptotic cell death...

  • Antizyme inhibitor 2: molecular, cellular and physiological aspects. López-Contreras, Andrés J.; Ramos-Molina, Bruno; Cremades, Asunción; Peñafiel, Rafael // Amino Acids;Feb2010, Vol. 38 Issue 2, p603 

    Polyamines are small organic polycations essential for cell proliferation and survival. Antizymes (AZs) are small proteins regulated by polyamines that inhibit polyamine biosynthesis and uptake in mammalian cells. In addition, antizyme functions are also regulated by antizyme inhibitors,...

  • The replication factory targeting sequence/PCNA-binding site is required in G1 to control the phosphorylation status of DNA ligase I. Rossi, Rossella; Villa, Antonello; Negri, Claudia; Scovassi, Ivana; Ciarrocchi, Giovanni; Biamonti, Giuseppe; Montecucco, Alessandra // EMBO Journal;10/15/99, Vol. 18 Issue 20, p5745 

    The recruitment of DNA ligase I to replication foci in S phase depends on a replication factory targeting sequence that also mediates the interaction with proliferating cell nuclear antigen (PCNA) in vitro. By exploiting a monoclonal antibody directed at a phospho-epitope, we demonstrate that...

  • Tracking of controlled Escherichia coli replication fork stalling and restart at repressor-bound DNA in vivo. Possoz, Christophe; Filipe, Sergio R; Grainge, Ian; Sherratt, David J // EMBO Journal;6/7/2006, Vol. 25 Issue 11, p2596 

    We report an efficient, controllable, site-specific replication roadblock that blocks cell proliferation, but which can be rapidly and efficiently reversed, leading to recovery of viability. Escherichia coli replication forks of both polarities stalled in vivo within the first 500 bp of a 10 kb...

  • Pharmacologic Characterization of [[superscript3]H]-Ifenprodil Binding to Polyamine Binding Sites on rabbit and Rat Retinal Homogenates: Role in Neuroprotection? Sharif, N.A.; Xu, S.X. // Journal of Ocular Pharmacology & Therapeutics;Jun99, Vol. 15 Issue 3, p271 

    Determines the presence of, and characterizes specific ³H;-ifenprodil binding sites on washed homogenates of rat and rabbit retinas. Equilibrium binding parameters for polyamine-sensitive ³H;-ifenprodil binding to rabbit and rat retinal homogenates; Affinities of polyamines and...

  • Low-Dose Diflouromethylornithine and Polyamine Levels in Human Prostate Tissue. Messing, Edward M.; Love, Richard R. // JNCI: Journal of the National Cancer Institute;08/18/99, Vol. 91 Issue 16, p1416 

    Features a study on the effects of difluoromethylornithine on human peripheral zone prostatic ornithine decarboxylate activities and polyamine levels in patients undergoing open prostatic surgery. Measurement of testosterone, prostate-specific antigen, and prostatic acid phosphatase levels;...

  • OAZ-t/OAZ3 Is Essential for Rigid Connection of Sperm Tails to Heads in Mouse. Tokuhiro, Keizo; Isotani, Ayako; Yokota, Sadaki; Yano, Yoshihisa; Oshio, Shigeru; Hirose, Mika; Wada, Morimasa; Fujita, Kyoko; Ogawa, Yukiko; Okabe, Masaru; Nishimune, Yoshitake; Tanaka, Hiromitsu // PLoS Genetics;Nov2009, Vol. 5 Issue 11, p1 

    Polyamines are known to play important roles in the proliferation and differentiation of many types of cells. Although considerable amounts of polyamines are synthesized and stored in the testes, their roles remain unknown. Ornithine decarboxylase antizymes (OAZs) control the intracellular...

  • The Polyamine Pathway as a Potential Target for Vascular Diseases: Focus on Restenosis. Forte, Amalia; Hellstrand, Per; Nilsson, Bengt-Olof; Grossi, Mario; Rossi, Francesco; Cipollaro, Marilena // Current Vascular Pharmacology;Nov2011, Vol. 9 Issue 6, p706 

    Polyamines are organic polycations expressed by all living organisms, which are known to play an essential role in cell proliferation and differentiation. Recent studies revealed their involvement also in cell contractility and migration and in programmed cell death. These processes are known to...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics