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Crystal structure of human myo-inositol monophosphatase 2, the product of the putative susceptibility gene for bipolar disorder, schizophrenia, and febrile seizures

Authors

  • Ryoichi Arai,

    1. Protein Research Group, RIKEN Genomic Sciences Center, Tsurumi, Yokohama 230-0045, Japan
    Current affiliation:
    1. Department of Chemistry, Princeton University, Princeton, NJ 08544-1009
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    • Ryoichi Arai and Kaori Ito contributed equally to this work.

  • Kaori Ito,

    1. Protein Research Group, RIKEN Genomic Sciences Center, Tsurumi, Yokohama 230-0045, Japan
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    • Ryoichi Arai and Kaori Ito contributed equally to this work.

  • Tetsuo Ohnishi,

    1. Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan
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  • Hisako Ohba,

    1. Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan
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  • Ryogo Akasaka,

    1. Protein Research Group, RIKEN Genomic Sciences Center, Tsurumi, Yokohama 230-0045, Japan
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  • Yoshitaka Bessho,

    1. Protein Research Group, RIKEN Genomic Sciences Center, Tsurumi, Yokohama 230-0045, Japan
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  • Kyoko Hanawa-Suetsugu,

    1. Protein Research Group, RIKEN Genomic Sciences Center, Tsurumi, Yokohama 230-0045, Japan
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  • Takeo Yoshikawa,

    1. Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan
    2. CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan
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  • Mikako Shirouzu,

    1. Protein Research Group, RIKEN Genomic Sciences Center, Tsurumi, Yokohama 230-0045, Japan
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  • Shigeyuki Yokoyama

    Corresponding author
    1. Protein Research Group, RIKEN Genomic Sciences Center, Tsurumi, Yokohama 230-0045, Japan
    2. Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Bunkyo, Tokyo 113-0033, Japan
    • Protein Research Group, Genomic Sciences Center, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan
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Abstract

The human IMPA2 gene, which encodes myo-inositol monophosphatase 2 (IMPA2), is mapped onto 18p11.2, a susceptibility region for bipolar disorder. This chromosomal region has also been proposed to include a susceptibility locus for schizophrenia and febrile seizures. Here we report the crystal structures of human IMPA2 and its complex with calcium and phosphate ions. Human IMPA2 comprises an α–β protein with a five-layered sandwich of α-helices and β-sheets (α–β–α–β–α). The crystal structure and analytical ultracentrifugation results indicated that IMPA2 exists as a dimer in solution. The overall structure of IMPA2 is similar to that of IMPA1, except for the loop regions. In IMPA1, the loop region (31–43) is located at the entrance of the active site cavity. In the corresponding region (42–54) of IMPA2, the residues are disordered and partially form an α-helix. The structural difference in the opening of the active site cavity suggests that the substrate specificity differs between IMPA1 and IMPA2. The widely opened cavity of IMPA2 implies that the physiological substrate may be a larger compound than inositol monophosphate. The structure of IMPA2 complexed with Ca2+ revealed two metals and one phosphate binding sites, which were the same sites as in IMPA1 complexed with Mn2+ and phosphate, suggesting that the mechanism of the enzymatic reaction is similar to that of IMPA1. The crystal structures of human IMPA2 are useful for understanding the effect of nonsynonymous polymorphism reported in IMPA2, and will contribute to further functional analyses of IMPA2 that potentially predisposes to the vulnerabilities of bipolar disorder, schizophrenia, and febrile seizures. Proteins 2007. © 2007 Wiley-Liss, Inc.

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