Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1

Egloff, Marie‐Pierre; Johnson, Deborah F.; Moorhead, Greg B. G.; Cohen, Patricia T.W.; Cohen, Philip; Barford, David

doi:10.1093/emboj/16.8.1876

Cited by 610 publications

(727 citation statements)

References 67 publications

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“…When compared to PLB, GM is a large protein of 1122 amino acids and it is established that its Nterminal stretch is responsible for the binding of the catalytic subunit PP1C [32,33]. A previous hydropathy analysis of the amino acid sequence of GM had revealed a hydrophobic region likely to anchor the protein to the membrane of the SR [12].…”

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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“…The PP1 consensus binding site has been thoroughly characterized in plethora of proteins and was accurately defined (Egloff et al, 1997). Presence of two PP1 docking motifs was identified in various PP1 binding proteins (Ayllon et al, 2002;Bennett and Alphey, 2002;Sugiyama et al, 2002;Garcia et al, 2003).…”

Section: Pp1a Associates With Fer and Is Downregulated In Fer-overexpmentioning

confidence: 99%

Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

et al. 2006

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Fer is a nuclear and cytoplasmic intracellular tyrosine kinase. Herein we show that Fer is required for cell-cycle progression in malignant cells. Decreasing the level of Fer using the RNA interference (RNAi) approach impeded the proliferation of prostate and breast carcinoma cells and led to their arrest at the G0/G1 phase. At the molecular level, knockdown of Fer resulted in the activation of the retinoblastoma protein (pRB), and this was reflected by profound hypo-phosphorylation of pRB on both cyclindependent kinase CDK4 and CDK2 phosphorylation sites. Dephosphorylation of pRB was not seen upon the direct targeting of either CDK4 or CDK2 expression, and was only partially achieved by the simultaneous depletion of these two kinases. Amino-acid sequence analysis revealed two protein phosphatase 1 (PP1) binding motifs in the kinase domain of Fer and the association of Fer with the pRB phosphatase PP1a was verified using co-immunoprecipitation analysis. Downregulation of Fer potentiated the activation of PP1a and overexpression of Fer decreased the enzymatic activity of that phosphatase. Our findings portray Fer as a regulator of cell-cycle progression in malignant cells and as a potential target for cancer intervention.

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“…These results strongly support the thesis that the binding of proteins to PP1 can be specified by presentation of this binding motif. During the course of this work, the crystal structure of PP1␦ in a complex with a peptide corresponding to the region on the muscle glycogen-binding subunit, G M , that had previously been implicated in binding to PP1 was determined (34). The crystal structure reveals that the sequence RRVSFA of G M binds in an extended conformation to a hydrophobic groove, adjacent to a region of acidic residues that accommodates the N-terminal basic residues.…”

Section: Table I Alignment Of Peptide Sequences That Bind To Pp1mentioning

confidence: 99%

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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Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1

Cited by 610 publications

References 67 publications

Biophysical interaction between phospholamban and protein phosphatase 1 regulatory subunit GM

Biophysical interaction between phospholamban and protein phosphatase 1 regulatory subunit GM

Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

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

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