The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Wolfgang Peti - One of the best experts on this subject based on the ideXlab platform.
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structural basis for Protein Phosphatase 1 regulation and specificity
FEBS Journal, 2013Co-Authors: Wolfgang Peti, Angus C. Nairn, Rebecca PageAbstract:The ubiquitous serine/threonine Protein Phosphatase 1 (PP1) regulates diverse, essential cellular processes such as cell cycle progression, Protein synthesis, muscle contraction, carbohydrate metabolism, transcription and neuronal signaling. However, the free catalytic subunit of PP1, while an effective enzyme, lacks substrate specificity. Instead, it depends on a diverse set of regulatory Proteins (≥ 200) to confer specificity towards distinct substrates. Here, we discuss recent advances in structural studies of PP1 holoenzyme complexes and summarize the new insights these studies have provided into the molecular basis of PP1 regulation and specificity.
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spinophilin directs Protein Phosphatase 1 specificity by blocking substrate binding sites
Nature Structural & Molecular Biology, 2010Co-Authors: Michael J Ragusa, Rebecca Page, Angus C. Nairn, Barbara Dancheck, David A Critton, Wolfgang PetiAbstract:Protein Phosphatase specificity is usually achieved via interaction with regulatory partners, which can control their subcellular localization and/or enzymatic specificity. Now structural and functional work on spinophilin reveals its extensive interactions with PP1, which differentially restrict the Phosphatase's ability to bind different substrates.
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detailed structural characterization of unbound Protein Phosphatase 1 inhibitors
Biochemistry, 2008Co-Authors: Barbara Dancheck, Angus C. Nairn, Wolfgang PetiAbstract:Protein Phosphatase 1 (PP1) is an essential and ubiquitous serine/threonine Protein Phosphatase that is regulated by more than 100 known inhibitor and targeting Proteins. It is currently unclear how Protein inhibitors distinctly and specifically regulate PP1 to enable rapid responses to cellular alterations. We demonstrate that two PP1 inhibitors, I-2 and DARPP-32, belong to the class of intrinsically unstructured Proteins (IUPs). We show that both inhibitors have distinct preferences for transient local and long-range structure. These preferences are likely their structural signature for their interaction with PP1. Furthermore, we show that upon phosphorylation of Thr34 in DARPP-32, which turns DARPP-32 into a potent inhibitor of PP1, neither local nor long-range structure of DARPP-32 is altered. Therefore, our data suggest a role for these transient three-dimensional topologies in binding mechanisms that enable extensive contacts with PP1’s invariant surfaces. Together, these interactions enable potent ...
Angus C. Nairn - One of the best experts on this subject based on the ideXlab platform.
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structural basis for Protein Phosphatase 1 regulation and specificity
FEBS Journal, 2013Co-Authors: Wolfgang Peti, Angus C. Nairn, Rebecca PageAbstract:The ubiquitous serine/threonine Protein Phosphatase 1 (PP1) regulates diverse, essential cellular processes such as cell cycle progression, Protein synthesis, muscle contraction, carbohydrate metabolism, transcription and neuronal signaling. However, the free catalytic subunit of PP1, while an effective enzyme, lacks substrate specificity. Instead, it depends on a diverse set of regulatory Proteins (≥ 200) to confer specificity towards distinct substrates. Here, we discuss recent advances in structural studies of PP1 holoenzyme complexes and summarize the new insights these studies have provided into the molecular basis of PP1 regulation and specificity.
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spinophilin directs Protein Phosphatase 1 specificity by blocking substrate binding sites
Nature Structural & Molecular Biology, 2010Co-Authors: Michael J Ragusa, Rebecca Page, Angus C. Nairn, Barbara Dancheck, David A Critton, Wolfgang PetiAbstract:Protein Phosphatase specificity is usually achieved via interaction with regulatory partners, which can control their subcellular localization and/or enzymatic specificity. Now structural and functional work on spinophilin reveals its extensive interactions with PP1, which differentially restrict the Phosphatase's ability to bind different substrates.
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detailed structural characterization of unbound Protein Phosphatase 1 inhibitors
Biochemistry, 2008Co-Authors: Barbara Dancheck, Angus C. Nairn, Wolfgang PetiAbstract:Protein Phosphatase 1 (PP1) is an essential and ubiquitous serine/threonine Protein Phosphatase that is regulated by more than 100 known inhibitor and targeting Proteins. It is currently unclear how Protein inhibitors distinctly and specifically regulate PP1 to enable rapid responses to cellular alterations. We demonstrate that two PP1 inhibitors, I-2 and DARPP-32, belong to the class of intrinsically unstructured Proteins (IUPs). We show that both inhibitors have distinct preferences for transient local and long-range structure. These preferences are likely their structural signature for their interaction with PP1. Furthermore, we show that upon phosphorylation of Thr34 in DARPP-32, which turns DARPP-32 into a potent inhibitor of PP1, neither local nor long-range structure of DARPP-32 is altered. Therefore, our data suggest a role for these transient three-dimensional topologies in binding mechanisms that enable extensive contacts with PP1’s invariant surfaces. Together, these interactions enable potent ...
Liming Wang - One of the best experts on this subject based on the ideXlab platform.
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pten l is a novel Protein Phosphatase for ubiquitin dephosphorylation to inhibit pink1 parkin mediated mitophagy
Cell Research, 2018Co-Authors: Liming Wang, Yiklam Cho, Yancheng Tang, Jigang Wang, Jung Eun Park, Chunxin Wang, Yan Tong, Ritu Chawla, Jianbin Zhang, Yin ShiAbstract:Mitophagy is an important type of selective autophagy for specific elimination of damaged mitochondria. PTEN-induced putative kinase Protein 1 (PINK1)-catalyzed phosphorylation of ubiquitin (Ub) plays a critical role in the onset of PINK1–Parkin-mediated mitophagy. Phosphatase and tensin homolog (PTEN)-long (PTEN-L) is a newly identified isoform of PTEN, with addition of 173 amino acids to its N-terminus. Here we report that PTEN-L is a novel negative regulator of mitophagy via its Protein Phosphatase activity against phosphorylated ubiquitin. We found that PTEN-L localizes at the outer mitochondrial membrane (OMM) and overexpression of PTEN-L inhibits, whereas deletion of PTEN-L promotes, mitophagy induced by various mitochondria-damaging agents. Mechanistically, PTEN-L is capable of effectively preventing Parkin mitochondrial translocation, reducing Parkin phosphorylation, maintaining its closed inactive conformation, and inhibiting its E3 ligase activity. More importantly, PTEN-L reduces the level of phosphorylated ubiquitin (pSer65-Ub) in vivo, and in vitro Phosphatase assay confirms that PTEN-L dephosphorylates pSer65-Ub via its Protein Phosphatase activity, independently of its lipid Phosphatase function. Taken together, our findings demonstrate a novel function of PTEN-L as a Protein Phosphatase for ubiquitin, which counteracts PINK1-mediated ubiquitin phosphorylation leading to blockage of the feedforward mechanisms in mitophagy induction and eventual suppression of mitophagy. Thus, understanding this novel function of PTEN-L provides a key missing piece in the molecular puzzle controlling mitophagy, a critical process in many important human diseases including neurodegenerative disorders such as Parkinson’s disease.
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pten l is a novel Protein Phosphatase for ubiquitin dephosphorylation to inhibit pink1 parkin mediated mitophagy
Cell Research, 2018Co-Authors: Liming Wang, Yancheng Tang, Jigang Wang, Jung Eun Park, Chunxin Wang, Yan Tong, Ritu Chawla, Jianbin Zhang, Yajun Wu, Shuo DengAbstract:Mitophagy is an important type of selective autophagy for specific elimination of damaged mitochondria. PTEN-induced putative kinase Protein 1 (PINK1)-catalyzed phosphorylation of ubiquitin (Ub) plays a critical role in the onset of PINK1–Parkin-mediated mitophagy. Phosphatase and tensin homolog (PTEN)-long (PTEN-L) is a newly identified isoform of PTEN, with addition of 173 amino acids to its N-terminus. Here we report that PTEN-L is a novel negative regulator of mitophagy via its Protein Phosphatase activity against phosphorylated ubiquitin. We found that PTEN-L localizes at the outer mitochondrial membrane (OMM) and overexpression of PTEN-L inhibits, whereas deletion of PTEN-L promotes, mitophagy induced by various mitochondria-damaging agents. Mechanistically, PTEN-L is capable of effectively preventing Parkin mitochondrial translocation, reducing Parkin phosphorylation, maintaining its closed inactive conformation, and inhibiting its E3 ligase activity. More importantly, PTEN-L reduces the level of phosphorylated ubiquitin (pSer65-Ub) in vivo, and in vitro Phosphatase assay confirms that PTEN-L dephosphorylates pSer65-Ub via its Protein Phosphatase activity, independently of its lipid Phosphatase function. Taken together, our findings demonstrate a novel function of PTEN-L as a Protein Phosphatase for ubiquitin, which counteracts PINK1-mediated ubiquitin phosphorylation leading to blockage of the feedforward mechanisms in mitophagy induction and eventual suppression of mitophagy. Thus, understanding this novel function of PTEN-L provides a key missing piece in the molecular puzzle controlling mitophagy, a critical process in many important human diseases including neurodegenerative disorders such as Parkinson’s disease.
Rene Bernards - One of the best experts on this subject based on the ideXlab platform.
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Protein Phosphatase 2a regulatory subunits and cancer
Biochimica et Biophysica Acta, 2009Co-Authors: Pieter Johan Adam Eichhorn, Menno P Creyghton, Rene BernardsAbstract:The serine/threonine Protein Phosphatase (PP2A) is a trimeric holoenzyme that plays an integral role in the regulation of a number of major signaling pathways whose deregulation can contribute to cancer. The specificity and activity of PP2A are highly regulated through the interaction of a family of regulatory B subunits with the substrates. Accumulating evidence indicates that PP2A acts as a tumor suppressor. In this review we summarize the known effects of specific PP2A holoenzymes and their roles in cancer relevant pathways. In particular we highlight PP2A function in the regulation of MAPK and Wnt signaling.
Barbara Dancheck - One of the best experts on this subject based on the ideXlab platform.
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spinophilin directs Protein Phosphatase 1 specificity by blocking substrate binding sites
Nature Structural & Molecular Biology, 2010Co-Authors: Michael J Ragusa, Rebecca Page, Angus C. Nairn, Barbara Dancheck, David A Critton, Wolfgang PetiAbstract:Protein Phosphatase specificity is usually achieved via interaction with regulatory partners, which can control their subcellular localization and/or enzymatic specificity. Now structural and functional work on spinophilin reveals its extensive interactions with PP1, which differentially restrict the Phosphatase's ability to bind different substrates.
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detailed structural characterization of unbound Protein Phosphatase 1 inhibitors
Biochemistry, 2008Co-Authors: Barbara Dancheck, Angus C. Nairn, Wolfgang PetiAbstract:Protein Phosphatase 1 (PP1) is an essential and ubiquitous serine/threonine Protein Phosphatase that is regulated by more than 100 known inhibitor and targeting Proteins. It is currently unclear how Protein inhibitors distinctly and specifically regulate PP1 to enable rapid responses to cellular alterations. We demonstrate that two PP1 inhibitors, I-2 and DARPP-32, belong to the class of intrinsically unstructured Proteins (IUPs). We show that both inhibitors have distinct preferences for transient local and long-range structure. These preferences are likely their structural signature for their interaction with PP1. Furthermore, we show that upon phosphorylation of Thr34 in DARPP-32, which turns DARPP-32 into a potent inhibitor of PP1, neither local nor long-range structure of DARPP-32 is altered. Therefore, our data suggest a role for these transient three-dimensional topologies in binding mechanisms that enable extensive contacts with PP1’s invariant surfaces. Together, these interactions enable potent ...
