Abstract
Serine/threonine protein phosphatase-5 (PP5) affects many signaling networks that regulate cell growth and cellular responses to stress. Here we report the crystal structure of the PP5 catalytic domain (PP5c) at a resolution of 1.6 A. From this structure we propose a mechanism for PP5-mediated hydrolysis of phosphoprotein substrates, which requires the precise positioning of two metal ions within a conserved Asp271-M1:M2-W1-His427-His304-Asp274 catalytic motif (where M1 and M2 are metals and W1 is a water molecule). The structure of PP5c provides a structural basis for explaining the exceptional catalytic proficiency of protein phosphatases, which are among the most powerful known catalysts. Resolution of the entire C terminus revealed a novel subdomain, and the structure of the PP5c should also aid development of type-specific inhibitors.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Binding Sites
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Catalysis
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Chemical Phenomena
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Chemistry, Physical
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Conserved Sequence
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Crystallization
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Crystallography, X-Ray
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Gene Expression
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Humans
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Hydrolysis
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Models, Molecular
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Molecular Structure
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Nuclear Proteins / chemistry*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Peptide Fragments / chemistry
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Peptide Fragments / genetics
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Phosphoprotein Phosphatases / chemistry*
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Phosphoprotein Phosphatases / genetics
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Phosphoprotein Phosphatases / metabolism*
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Recombinant Fusion Proteins
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Sequence Alignment
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Static Electricity
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Structure-Activity Relationship
Substances
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Nuclear Proteins
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Peptide Fragments
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Recombinant Fusion Proteins
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Phosphoprotein Phosphatases
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protein phosphatase 5