Crystal structure of human ornithine decarboxylase at 2.1 A 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 decarboxylation of ornithine to putrescine. Elevated polyamine levels can lead to down-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 A resolution by molecular replacement using truncated mouse ODC (Delta425-461) as the search model and refined to a crystallographic R-factor of 21.2% and an R-free value of 28.8%. The human ODC model includes several regions that are disordered in the mouse ODC crystal structure, including one of two C-terminal basal degradation elements that have been demonstrated to independently collaborate with antizyme binding to target ODC for degradation by the 26S proteasome. The crystal structure of human ODC suggests that the C terminus, which contains basal degradation elements necessary for antizyme-induced proteolysis, is not buried by the structural core of homodimeric ODC as previously proposed. Analysis of the solvent-accessible surface area, surface electrostatic 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.
Almrud
J J
JJ
Department of Chemistry, The University of Texas at Austin, Austin, TX, 78712, USA.
Oliveira
M A
MA
Kern
A D
AD
Grishin
N V
NV
Phillips
M A
MA
Hackert
M L
ML
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008099:Liver / Q000201:enzymology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009955:Ornithine Decarboxylase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism; D011487:Protein Conformation; D011506:Proteins / Q000378:metabolism; D016415:Sequence Alignment; D012997:Solvents; D055672:Static Electricity; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000201:enzymology
D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D011506:Proteins; D012997:Solvents; C031017:ornithine decarboxylase antizyme; D009955:Ornithine Decarboxylase