Substrate-dependent metal preference of PPM1H, a cancer-associated protein phosphatase 2C: comparison with other family members |
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Authors: | Takeyuki Sugiura Yoshie Noguchi |
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Institution: | (1) Discovery Research Laboratory, Tokyo R&D Center, Daiichi Pharmaceutical Co., Ltd., Daiichi-Sankyo Group, Tokyo, Japan;(2) Present address: Exploratory Research Laboratories II, Kasai R&D Center, Daiichi-Sankyo Co., Ltd., 16-13, Kitakasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan |
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Abstract: | Protein phosphatase 2C (PP2C) family is characterized by requirement of metal cation for phosphatase activity. We previously
established that PPM1H is a cancer-associated member of the PP2C family. Here we further characterized the phosphatase activity
of PPM1H, focusing on its dependence on metal cation. PPM1H possesses the potential to dephosphorylate p-nitrophenyl phosphate (pNPP), casein and phosphopeptides. Interestingly, PPM1H shows the metal preference that is varied
depending on the substrate (substrate-dependent metal preference); PPM1H prefers Mn2+ when pNPP or phosphopeptides is used as a substrate. Meanwhile, a preference for Mg2+ is displayed by PPM1H with casein as a substrate. When both cations are added to the reaction, the degree of the effect is
always closer to that with Mn2+ alone, irrespective of the substrate. This preponderance of Mn2+ is explained by its greater affinity for PPM1H than Mg2+. From the literature the substrate-dependent metal preference appears to be shared by other PP2Cs. According to the crystal
structure, a binuclear metal center of PP2C plays an important role for coordinating the substrate and nucleophilic waters
in the active site. Therefore, the differences in the size, preferred geometry and coordination requirements between two metals,
in relation to the substrate, may be responsible for this intriguing property. |
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Keywords: | Catalytic domain Metal cation cofactor PPM1H Protein phosphatase 2C |
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