Crystal structure of human ornithine decarboxylase at 2.1 angstrom resolution: Structural insights to antizyme binding

The polyamines spermidine and spermine are ubiquitous and required for cell growth and differentiation in eukaryotes. Ornithine decarboxylase (ODC, EC 4.1.1.17) performs the first step in polyamine biosynthesis, the decarboxy lation of ornithine to putrescine. Elevated polyamine levels can lead to do wn-regulation of ODC activity by enhancing the translation of antizyme mRNA , resulting in subsequent binding of antizyme to ODC monomers which targets ODC for proteolysis by the 26S proteasome. The crystal structure of ornithine decarboxylase from human liver has been determined to 2.1 Angstrom resolution by molecular replacement using trunca ted mouse ODC (Delta 425-461) as the search model and refined to a crystall ographic R-factor of 21.2% and an R-free value of 28.8%. The human ODC mode l includes several regions that are disordered in the mouse ODP crystal str ucture, including one of two C-terminal basal degradation elements that hav e been demonstrated to independently collaborate with antizyme binding to t arget ODC for degradation by the 26S proteasome. The crystal structure of human ODC suggests that the C terminus, which cont ains basal degradation elements necessary for antizyme-induced proteolysis, is not buried by the structural core of homodimeric ODC as previously prop osed. Analysis of the solvent-accessible surface area, surface electrostati c potential, and the conservation of primary sequence between human ODC and Trypanosoma brucei ODC provides clues to the identity of potential protein -binding-determinants in the putative antizyme binding element in human ODC . (C) 2000 Academic Press.