Biogenesis and activity regulation of protein phosphatase 1

Protein phosphatase 1 (PP1) is expressed in all eukaryotic cells and catalyzes a substantial fraction of phosphoserine/threonine dephosphorylation reactions. It forms stable complexes with PP1-interacting proteins (PIPs) that guide the phosphatase throughout its life cycle and control its fate and function. The diversity of PIPs is huge (≈200 in vertebrates), and most of them combine short linear motifs to form large and unique interaction interfaces with PP1. Many PIPs have separate domains for PP1 anchoring, PP1 regulation, substrate recruitment and subcellular targeting, which enable them to direct associated PP1 to a specific subset of substrates and mediate acute activity control. Hence, PP1 functions as the catalytic subunit of a large number of multimeric holoenzymes, each with its own subset of substrates and mechanism(s) of regulation.

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Phosphorylation and dephosphorylation of Ser852 and Ser889 control the clustering, localization and function of PAR3

Journal of Cell Science ◽

10.1242/jcs.244830 ◽

2020 ◽

Vol 133 (22) ◽

pp. jcs244830

Author(s):

Kazunari Yamashita ◽

Keiko Mizuno ◽

Kana Furukawa ◽

Hiroko Hirose ◽

Natsuki Sakurai ◽

...

Keyword(s):

Tight Junction ◽

Protein Phosphatase ◽

Phosphorylation Site ◽

Protein Phosphatase 1 ◽

Membrane Domain ◽

Unique Role ◽

Cellular Events ◽

Local Clustering ◽

And Function ◽

Specific Membrane

ABSTRACTCell polarity is essential for various asymmetric cellular events, and the partitioning defective (PAR) protein PAR3 (encoded by PARD3 in mammals) plays a unique role as a cellular landmark to establish polarity. In epithelial cells, PAR3 localizes at the subapical border, such as the tight junction in vertebrates, and functions as an apical determinant. Although we know a great deal about the regulators of PAR3 localization, how PAR3 is concentrated and localized to a specific membrane domain remains an important question to be clarified. In this study, we demonstrate that ASPP2 (also known as TP53BP2), which controls PAR3 localization, links PAR3 and protein phosphatase 1 (PP1). The ASPP2–PP1 complex dephosphorylates a novel phosphorylation site, Ser852, of PAR3. Furthermore, Ser852- or Ser889-unphosphorylatable PAR3 mutants form protein clusters, and ectopically localize to the lateral membrane. Concomitance of clustering and ectopic localization suggests that PAR3 localization is a consequence of local clustering. We also demonstrate that unphosphorylatable forms of PAR3 exhibited a low molecular turnover and failed to coordinate rapid reconstruction of the tight junction, supporting that both the phosphorylated and dephosphorylated states are essential for the functional integrity of PAR3.

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The Physiological Relevance of Protein Phosphatase 1 and its Interacting Proteins to Health and Disease

Current Medicinal Chemistry ◽

10.2174/092986710793205363 ◽

2012 ◽

Vol 17 (33) ◽

pp. 3996-4017 ◽

Cited By ~ 39

Author(s):

M. Fardilha ◽

S. L.C. Esteves ◽

L. Korrodi-Gregorio ◽

O. A.B. da Cruz e Silva ◽

E. F. da Cruz e Silva

Keyword(s):

Protein Phosphatase ◽

Protein Phosphatase 1 ◽

Interacting Proteins ◽

Physiological Relevance ◽

Health And Disease

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Role of Protein Phosphatase‐1 Inhibitor‐3 in the Isoform‐Selective Expression, Subcellular Targeting and Nuclear/Nucleolar Transport of Protein Phosphatase‐1

The FASEB Journal ◽

10.1096/fasebj.20.5.lb64-a ◽

2006 ◽

Vol 20 (5) ◽

Author(s):

Hua‐Shan Huang ◽

Ernest Y.C. Lee

Keyword(s):

Protein Phosphatase ◽

Protein Phosphatase 1 ◽

Subcellular Targeting ◽

Selective Expression

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Regulation and Function of the Muscle Glycogen-Targeting Subunit of Protein Phosphatase 1 (GM) in Human Muscle Cells Depends on the COOH-Terminal Region and Glycogen Content

Diabetes ◽

10.2337/diabetes.52.9.2221 ◽

2003 ◽

Vol 52 (9) ◽

pp. 2221-2226 ◽

Cited By ~ 13

Author(s):

C. Lerin ◽

E. Montell ◽

T. Nolasco ◽

C. Clark ◽

M. J. Brady ◽

...

Keyword(s):

Muscle Glycogen ◽

Protein Phosphatase ◽

Glycogen Content ◽

Muscle Cells ◽

Human Muscle ◽

Terminal Region ◽

Protein Phosphatase 1 ◽

And Function ◽

Human Muscle Cells

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Quantitative mapping of protein-peptide affinity landscapes using spectrally encoded beads

eLife ◽

10.7554/elife.40499 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 14

Author(s):

Huy Quoc Nguyen ◽

Jagoree Roy ◽

Björn Harink ◽

Nikhil P Damle ◽

Naomi R Latorraca ◽

...

Keyword(s):

Protein Phosphatase ◽

Signaling Networks ◽

Energy Landscapes ◽

Post Translational Modifications ◽

Short Linear Motifs ◽

Quantitative Mapping ◽

Wide Range ◽

Binding Peptides ◽

Linear Motifs ◽

Peptide Affinity

Transient, regulated binding of globular protein domains to Short Linear Motifs (SLiMs) in disordered regions of other proteins drives cellular signaling. Mapping the energy landscapes of these interactions is essential for deciphering and perturbing signaling networks but is challenging due to their weak affinities. We present a powerful technology (MRBLE-pep) that simultaneously quantifies protein binding to a library of peptides directly synthesized on beads containing unique spectral codes. Using MRBLE-pep, we systematically probe binding of calcineurin (CN), a conserved protein phosphatase essential for the immune response and target of immunosuppressants, to the PxIxIT SLiM. We discover that flanking residues and post-translational modifications critically contribute to PxIxIT-CN affinity and identify CN-binding peptides based on multiple scaffolds with a wide range of affinities. The quantitative biophysical data provided by this approach will improve computational modeling efforts, elucidate a broad range of weak protein-SLiM interactions, and revolutionize our understanding of signaling networks.

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The structure of SDS22 provides insights into the mechanism of heterodimer formation with PP1

Acta Crystallographica Section F Structural Biology Communications ◽

10.1107/s2053230x18016503 ◽

2018 ◽

Vol 74 (12) ◽

pp. 817-824 ◽

Cited By ~ 1

Author(s):

Meng S. Choy ◽

Nicolas Bolik-Coulon ◽

Tara L. Archuleta ◽

Wolfgang Peti ◽

Rebecca Page

Keyword(s):

Protein Phosphatase ◽

Intrinsically Disordered Proteins ◽

Regulatory Proteins ◽

Protein Phosphatase 1 ◽

Disordered Proteins ◽

Biological Targets ◽

Intrinsically Disordered ◽

Intrinsically Disordered Regions ◽

Linear Motifs ◽

Lrr Protein

Protein phosphatase 1 (PP1) dephosphorylates hundreds of key biological targets by associating with nearly 200 regulatory proteins to form highly specific holoenzymes. The vast majority of regulators are intrinsically disordered proteins (IDPs) and bind PP1 via short linear motifs within their intrinsically disordered regions. One of the most ancient PP1 regulators is SDS22, a protein that is conserved from yeast to mammals. Sequence analysis of SDS22 revealed that it is a leucine-rich repeat (LRR) protein, suggesting that SDS22, unlike nearly every other known PP1 regulator, is not an IDP but instead is fully structured. Here, the 2.9 Å resolution crystal structure of human SDS22 in space group P212121 is reported. SDS22 adopts an LRR fold with the horseshoe-like curvature typical for this family of proteins. The structure results in surfaces with distinct chemical characteristics that are likely to be critical for PP1 binding.

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