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A voltage-sensing phosphatase, Ci-VSP, dephosphorylates phosphatidylinositol 4,5-bisphosphate

2008년 8월 12일 14시 57분 24초
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목 <발표Ⅰ>
저자 및
Hirohide Iwasaki, Yoshimichi Murata, 김영준1, Md. Israil Hossain, Carolyn Worby2, Jack E. Dixon2, Thomas McCormack, Takehiko Sasaki, Yasushi Okamura
Okazaki Center for Integrative Biosciences, Japan
1건국대학교 응용생화학과, Korea
2University of California, San Diego, United States
Phosphatidylinositol lipids play diverse physiological roles and their concentrations are tightly regulated by various kinases and phosphatases. The enzymatic activity of Ciona intestinalis voltage sensor-containing phosphatase (Ci-VSP), recently identified as a member of the PTEN family of phosphatidylinositol phosphatases, was shown to be regulated by its own voltage-sensor domain in a voltage-dependent manner. However, a detailed mechanism of Ci-VSP regulation and its substrate specificity remain unknown. Here we determined the in vitro substrate specificity of Ci-VSP by measuring the phosphoinositide phosphatase activity of its purified cytoplasmic phosphatase domain. Despite the high degree of identity shared between the active sites of PTEN and Ci-VSP, Ci-VSP dephosphorylates not only the PTEN substrate, phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3), but also phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). Enzymatic action on PI(4,5)P2 removes the phosphate at position 5 of the inositol ring, resulting in the production of phosphatidylinositol 4-phosphate (PI(4)P). The active site Cys-X5-Arg (CX5R) sequence of Ci-VSP differs with that of PTEN only at amino acid 365 where a glycine residue in Ci-VSP is replaced by an alanine in PTEN. Ci-VSP with a G365A mutation no longer dephosphorylated PI(4,5)P2 but retained activity toward PI(3,4,5)P3 demonstrating that this residue is critical for substrate specificity. These results indicate that VSP is a PI(3,4,5)P3/PI(4,5)P2 phosphatase and that the glycine residue in the CX5R sequence of the enzyme active site is critical for the unique function of Ci-VSP: the voltage dependent regulation of ion channels through regulation of PI(4,5)P2 levels.