PTG, a Protein Phosphatase 1-Binding Protein with a Role in Glycogen Metabolism

Printen, John A.; Brady, Matthew J.; Saltiel, Alan R.

doi:10.1126/science.275.5305.1475

Cited by 277 publications

(307 citation statements)

References 19 publications

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“…In addition to targeting PP1 to the glycogen particle, PTG can also form complexes with PP1 substrate enzymes that regulate glycogen metabolism, namely glycogen synthase, glycogen phosphorylase, and phosphorylase kinase. In this case, PTG not only binds PP1C and glycogen but also co-localises PP1 with its substrate at the glycogen particles suggesting that PTG is responsible for assembling metabolic enzymes for the localised reception of intracellular signals [23,24]. In a similar way, the present experiments suggest that GM, which targets PP1C to both glycogen particles and the SR of striated muscle [13], may localise PP1C close to its PLB substrate in order to control speci¢cally the activation of the calcium ATPase.…”

Section: Discussionmentioning

confidence: 99%

Biophysical interaction between phospholamban and protein phosphatase 1 regulatory subunit GM

Berrebi-Bertrand¹,

Souchet²,

Camelin³

et al. 1998

FEBS Letters

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Regulation of the sarco(endo)plasmic reticulum Ca P+ -ATPase (SERCA 2a) depends on the phosphorylation state of phospholamban (PLB). When PLB is phosphorylated, its inhibitory effect towards SERCA 2a is relieved, leading to an enhanced myocardial performance. This process is reversed by a sarcoplasmic reticulum (SR)-associated type 1 protein phosphatase (PP1) composed of a catalytic subunit PP1C and a regulatory subunit GM. Human GM and PLB have been produced in an in vitro transcription/translation system and used for co-immunoprecipitation and biosensor experiments. The detected interaction between the two partners suggests that cardiac PP1 is targeted to PLB via GM and we believe that this process occurs with the identified transmembrane domains of the two proteins. Thus, the interaction between PLB and GM may represent a specific way to modulate the SR function in human cardiac muscle.z 1998 Federation of European Biochemical Societies.

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Section: Discussionmentioning

confidence: 99%

Biophysical interaction between phospholamban and protein phosphatase 1 regulatory subunit GM

Berrebi-Bertrand¹,

Souchet²,

Camelin³

et al. 1998

FEBS Letters

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Section: Nih Public Accessmentioning

confidence: 99%

“…Another connection to glycogen came from the yeast two hybrid screen described by Fernandez-Sanchez et al [18] which identified the type 1 protein serine/threonine phosphatase regulatory subunit, PTG. PTG, also called R5, binds glycogen and is implicated in the control of glycogen metabolism [24]. PTG has been proposed to act as a scaffold, binding also to glycogen synthase, phosphorylase and phosphorylase kinase [24].…”

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confidence: 99%

“…PTG, also called R5, binds glycogen and is implicated in the control of glycogen metabolism [24]. PTG has been proposed to act as a scaffold, binding also to glycogen synthase, phosphorylase and phosphorylase kinase [24]. Fernandez-Sanchez et al [18] found that a disease-associated mutation of laforin, G240S, has no effect on either phosphatase activity or glycogen binding but impairs interaction with PTG.…”

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confidence: 99%

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Glycogen metabolism in tissues from a mouse model of Lafora disease

Wang

Lohi

Skurat

et al. 2007

Archives of Biochemistry and Biophysics

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Laforin, encoded by the EPM2A gene, by sequence is a member of the dual specificity protein phosphatase family. Mutations in the EPM2A gene account for around half of the cases of Lafora disease, an autosomal recessive neurodegenerative disorder, characterized by progressive myoclonus epilepsy. The hallmark of the disease is the presence of Lafora bodies, which contain polyglucosan, a poorly branched form of glycogen, in neurons, muscle and other tissues. Glycogen metabolizing enzymes were analyzed in a transgenic mouse over-expressing a dominant negative form of laforin that accumulates Lafora bodies in several tissues. Skeletal muscle glycogen was increased two-fold as was the total glycogen synthase protein. However, the −/+ glucose-6-P activity of glycogen synthase was decreased from 0.29 to 0.16. Branching enzyme activity was increased by 30%. Glycogen phosphorylase activity was unchanged. In whole brain, no differences in glycogen synthase or branching enzyme activities were found. Although there were significant differences in enzyme activities in muscle, the results do not support the hypothesis that Lafora body formation is caused by a major change in the balance between glycogen elongation and branching activities.Lafora disease is an autosomal recessive, progressive myoclonus epilepsy (OMIM #254780), with onset typically in teenagers followed by decline and death usually within ten years [1][2][3]. The disease is characterized by the presence of Lafora bodies, periodic acid-Schiff positive structures containing an abnormal form of glycogen, the branched polymer of glucose that serves as a stored form of glucose in many tissues. Although Lafora body formation in neurons is believed to account for the symptoms of the disease, the bodies are present in other tissues including liver, muscle and skin [4][5][6][7].Glycogen synthesis (Fig. 1) is mediated by glycogen synthase, which catalyzes formation of the predominant α-1,4-glycosidic linkage of the polymer and branching enzyme, which introduces the α-1,6-glycosidic branchpoints [8]. Degradation occurs in the cytosol through the action of glycogen phosphorylase and the debranching enzyme or alternatively in the lysosome via the activity of an α-glycosidase (acid maltase or GAA). In Lafora disease, a less ¶Correspondence to: Peter J. Roach, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5122, Phone 317 274-1582, FAX 317 274-4686, E-mail proach@iupui.edu. 1 Present address: Department of Medicine, University of California, San Diego, USA Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal di...

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“…These include genes that are variously required for control of glycogen metabolism, glucose repression, meiosis and/or sporulation, and mitotic cell cycle regulation (19 -21). Thus, PP1 is unusual in that this single enzyme is involved in the regulation of a number of diverse cellular processes.Few, if any, of the PP1 proteins share any major sequence identity, although examination of different glycogen-binding subunits has revealed the presence of two small regions of sequence similarity that is shared between several glycogenbinding proteins (20,(22)(23)(24)(25). The unusually large number of PP1-binding proteins that have been described suggests either that PP1 contains a motif that is recognized by a common binding structure on this diverse group of proteins or that the latter contain a protein motif that is recognized by a single binding site on PP1.…”

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A Protein Phosphatase-1-binding Motif Identified by the Panning of a Random Peptide Display Library

Zhao

Lee

1997

Journal of Biological Chemistry

133

125

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An unusually large number of regulatory or targeting proteins that bind to the catalytic subunit of protein phosphatase-1 have been recently reported. This can be explained by their possession of a common protein motif that interacts with a binding site on protein phosphatase-1. The existence of such a motif was established by the panning of a random peptide library in which peptide sequences are displayed on the Escherichia coli bacterial flagellin protein for bacteria that bound to protein phosphatase-1. There were 79 isolates containing 46 unique sequences with the conserved motif VXF or VXW, where X was most frequently His or Arg. In addition, this sequence was commonly preceded by 2-5 basic residues and followed by 1 acidic residue. This study demonstrates that binding to protein phosphatase-1 can be conferred to a protein by the presentation of a peptide motif on a surface loop. This binding motif is found in a number of protein phosphatase-1-binding proteins.Protein phosphatase-1, originally studied in the context of glycogen metabolism as the enzyme that converts phosphorylase a to phosphorylase b (1), has been implicated in the regulation of a number of important cellular processes (for reviews, see Refs. 2 and 3). Biochemical studies have revealed that it consists of a catalytic subunit (4 -7) of 37 kDa (PP1) 1 that forms a number of heterodimeric enzymes with different subunits, which include a glycogen-binding subunit, a myosin-binding subunit (8), and inhibitor-2 (9). These subunits function to target the catalytic subunit to the subcellular or molecular proximity of its substrates and may serve to provide regulation of activity as well as modulation of substrate specificity (8). In addition, PP1 is regulated by several inhibitory proteins; these include inhibitor-1 (10), DARPP-32 (10), inhibitor-2 and NIPP (a nuclear inhibitory protein) (11). The use of the yeast twohybrid system has led to the discovery of a surprisingly large number of PP1-binding proteins. Mammalian PP1-binding proteins include the retinoblastoma gene product (12), HSP78 (13), p53BP2 (14), splicing factor PSF (15), ribosomal protein L5 (16), herpesvirus ␥ 1 34.5 protein (17), and HOX11 (18). In yeast, over a dozen genes that encode PP1-binding proteins have been identified, based largely on the use of a two-hybrid screen. These include genes that are variously required for control of glycogen metabolism, glucose repression, meiosis and/or sporulation, and mitotic cell cycle regulation (19 -21). Thus, PP1 is unusual in that this single enzyme is involved in the regulation of a number of diverse cellular processes.Few, if any, of the PP1 proteins share any major sequence identity, although examination of different glycogen-binding subunits has revealed the presence of two small regions of sequence similarity that is shared between several glycogenbinding proteins (20,(22)(23)(24)(25). The unusually large number of PP1-binding proteins that have been described suggests either that PP1 contains a motif that is recognized by a common...

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PTG, a Protein Phosphatase 1-Binding Protein with a Role in Glycogen Metabolism

Cited by 277 publications

References 19 publications

Biophysical interaction between phospholamban and protein phosphatase 1 regulatory subunit GM

Biophysical interaction between phospholamban and protein phosphatase 1 regulatory subunit GM

Glycogen metabolism in tissues from a mouse model of Lafora disease

A Protein Phosphatase-1-binding Motif Identified by the Panning of a Random Peptide Display Library

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