ScienceDaily (Mar. 29, 2010) — Protein phosphorylation is a process by which proteins are flipped from one activation state to another. It is a crucial function for most living beings, since phosphorylation controls nearly every cellular process, including metabolism, gene transcription, cell-cycle progression, cytoskeletal rearrangement and cell movement.
The Master Regulator Research led by Wolfgang Peti of Brown University shows how a phosphatase called PP1 becomes more selective in protein-protein interactions. In the illustration, the phosphate spinophilin binds to one of PP1's three available binding sites, reducing the number of available substrates for other proteins. (Credit: Wolfgang Peti, Brown University)
The question then is how PP1, a generalist, knows which substrate proteins to interact with. New research by Wolfgang Peti, the Manning Assistant Professor of Medical Science and assistant professor of chemistry, reported in a paper published online in Nature Structural & Molecular Biology, helps to answer that question. Peti and colleagues at Brown and Yale University have discovered that PP1 "chooses" proteins in dephosphorylation reactions based on which of its binding sites is available for the interaction to occur. The finding is important, because erroneous PP1 regulation can cause numerous diseases, including cancer (chromatin remodeling), diabetes (glycogen) and Parkinson's (LTP).
"There are thousands of (peer-reviewed) papers out there, but nobody understood how PP1 is regulated," said Peti. "It is in fact a master regulator. We have identified now how it works."
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Nature Structural & Molecular Biology
Published online: 21 March 2010 | doi:10.1038/nsmb.1786
Spinophilin directs protein phosphatase 1 specificity by blocking substrate binding sites
Michael J Ragusa1,2, Barbara Dancheck1, David A Critton2, Angus C Nairn3, Rebecca Page2 & Wolfgang Peti1
Abstract
The serine/threonine protein phosphatase 1 (PP1) dephosphorylates hundreds of key biological targets. PP1 associates with ≥200 regulatory proteins to form highly specific holoenzymes. These regulatory proteins target PP1 to its point of action within the cell and prime its enzymatic specificity for particular substrates. However, how they direct PP1's specificity is not understood. Here we show that spinophilin, a neuronal PP1 regulator, is entirely unstructured in its unbound form, and it binds PP1 through a folding-upon-binding mechanism in an elongated fashion, blocking one of PP1's three putative substrate binding sites without altering its active site. This mode of binding is sufficient for spinophilin to restrict PP1's activity toward a model substrate in vitro without affecting its ability to dephosphorylate its neuronal substrate, glutamate receptor 1 (GluR1). Thus, our work provides the molecular basis for the ability of spinophilin to dictate PP1 substrate specificity.
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Professores, pesquisadores e alunos de universidades públicas e privadas com acesso ao site CAPES/Periódicos podem ler gratuitamente este artigo da Nature Structural & Molecular Biology e de mais 22.440 publicações científicas.
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Nature Structural & Molecular Biology
Published online: 21 March 2010 | doi:10.1038/nsmb.1786
Spinophilin directs protein phosphatase 1 specificity by blocking substrate binding sites
Michael J Ragusa1,2, Barbara Dancheck1, David A Critton2, Angus C Nairn3, Rebecca Page2 & Wolfgang Peti1
Abstract
The serine/threonine protein phosphatase 1 (PP1) dephosphorylates hundreds of key biological targets. PP1 associates with ≥200 regulatory proteins to form highly specific holoenzymes. These regulatory proteins target PP1 to its point of action within the cell and prime its enzymatic specificity for particular substrates. However, how they direct PP1's specificity is not understood. Here we show that spinophilin, a neuronal PP1 regulator, is entirely unstructured in its unbound form, and it binds PP1 through a folding-upon-binding mechanism in an elongated fashion, blocking one of PP1's three putative substrate binding sites without altering its active site. This mode of binding is sufficient for spinophilin to restrict PP1's activity toward a model substrate in vitro without affecting its ability to dephosphorylate its neuronal substrate, glutamate receptor 1 (GluR1). Thus, our work provides the molecular basis for the ability of spinophilin to dictate PP1 substrate specificity.
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Professores, pesquisadores e alunos de universidades públicas e privadas com acesso ao site CAPES/Periódicos podem ler gratuitamente este artigo da Nature Structural & Molecular Biology e de mais 22.440 publicações científicas.
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