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Published online before print March 27, 2008
Protein Science, DOI: 10.1110/ps.073427208
 Copyright © 2008 The Protein Society
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Crystallographic and biochemical studies revealing the structural basis for antizyme inhibitor function

Shira Albeck1,3, Orly Dym1,3, Tamar Unger1,3, Zohar Snapir2, Zippy Bercovich2, and Chaim Kahana2

1 The Israel Structural Proteomics Center, Weizmann Institute of Science, Rehovot 76100, Israel
2 Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel

(RECEIVED December 26, 2007; FINAL REVISION January 28, 2008; ACCEPTED January 29, 2008)

Antizyme inhibitor (AzI) regulates cellular polyamine homeostasis by binding to the polyamine-induced protein, Antizyme (Az), with greater affinity than ornithine decarboxylase (ODC). AzI is highly homologous to ODC but is not enzymatically active. In order to understand these specific characteristics of AzI and its differences from ODC, we determined the 3D structure of mouse AzI to 2.05 Å resolution. Both AzI and ODC crystallize as a dimer. However, fewer interactions at the dimer interface, a smaller buried surface area, and lack of symmetry of the interactions between residues from the two monomers in the AzI structure suggest that this dimeric structure is nonphysiological. In addition, the absence of residues and interactions required for pyridoxal 5'-phosphate (PLP) binding suggests that AzI does not bind PLP. Biochemical studies confirmed the lack of PLP binding and revealed that AzI exists as a monomer in solution while ODC is dimeric. Our findings that AzI exists as a monomer and is unable to bind PLP provide two independent explanations for its lack of enzymatic activity and suggest the basis for its enhanced affinity toward Az.

Keywords: structure/function studies; protein crystallization; protein structures–new; antizyme inhibitor; antizyme; ornithine decarboxylase

3 These authors contributed equally to this work.

Reprint requests to: Chaim Kahana, Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel; e-mail: chaim.kahana{at}weizmann.ac.il; fax: +972-8-9344199.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.073427208.


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