Flexibility in the PP1:spinophilin holoenzyme

Ragusa, Michael J.; Allaire, Marc; Nairn, Angus C.; Page, Rebecca; Peti, Wolfgang

doi:10.1016/j.febslet.2010.11.022

Cited by 22 publications

(19 citation statements)

References 20 publications

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“…NMR spectroscopy allowed us to obtain a detailed view of the regions involved in the interaction of PfI2 with PfPP1. The weak dispersion of the signals on the 1 H scale in the 1 H-15 N HSQC, and the values of the CA and CB chemical shifts indicate a globally disordered protein, as observed for numerous PP1 regulators [37][38][39][40][41]. However, assignment of the chemical shift resonances for all the residues in the 3D experiments was not feasible because of resonance broadening localized in specific regions of the protein.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Plasmodium falciparum inhibitor‐2 motif involved in the binding and regulation activity of protein phosphatase type 1

et al. 2014

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Section: Discussionmentioning

confidence: 99%

Identification of a Plasmodium falciparum inhibitor‐2 motif involved in the binding and regulation activity of protein phosphatase type 1

et al. 2014

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“…Whereas numerous IDP protein–protein interactions have been reported and analysed in the last 15 years, in the present review, we focus on three distinct IDPs that bind the same well-folded enzyme, PP1: the PP1-targeting proteins spinophilin [19,33,34] and MYPT1 [35,36], and the PP1 inhibitor I-2 [17,19,37,38]. When these proteins bind PP1 to form a PP1 holoenzyme, PP1 becomes highly specific for a subset of substrates (Figures 1 and 2).…”

Section: The Biophysical Behaviour Of Idpsmentioning

confidence: 99%

Regulation of protein phosphatase 1 by intrinsically disordered proteins

Choy

Page

Peti

2012

Biochemical Society Transactions

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PP1 (protein phosphatase 1) is an essential serine/threonine phosphatase that plays a critical role in a broad range of biological processes, from muscle contraction to memory formation. PP1 achieves its biological specificity by forming holoenzymes with more than 200 known regulatory proteins. Interestingly, most of these regulatory proteins (≥70%) belong to the class of IDPs (intrinsically disordered proteins). Thus structural studies highlighting the interaction of these IDP regulatory proteins with PP1 are an attractive model system because it allows general parameters for a group of diverse IDPs that interact with the same binding partner to be identified, while also providing fundamental insights into PP1 biology. The present review provides a brief overview of our current understanding of IDP–PP1 interactions, including the importance of pre-formed secondary and tertiary structures for PP1 binding, as well as changes of IDP dynamics upon interacting with PP1.

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“…Structural information for the PP1 holoenzyme has only recently started to emerge, e.g. MyPT1: PP1 (PDB code 1s70) [92,93], spinophilin:PP1 (PDB code 3egg) [94][95][96], neurabin:PP1 (PDB code 3hvq) [94] and NIPP1:PP1 (PDB code 3v4y) [97].…”

Section: Pp1 Inhibitorsmentioning

confidence: 99%

Viewing serine/threonine protein phosphatases through the eyes of drug designers

et al. 2013

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Protein phosphatases, as the counterpart to protein kinases, are essential for homeostatic balance of cell signaling. Small chemical compounds that modulate the specific activity of phosphatases can be powerful tools to elucidate the biological functions of these enzymes. More importantly, many phosphatases are central players in the development of pathological pathways where inactivation can reverse or delay the onset of human diseases. Therefore, potent inhibitors for such phosphatases can be of great therapeutic benefit. In contrast to the seemingly identical enzymatic mechanism and structural characterization of eukaryotic protein kinases, protein phosphatases evolved from diverse ancestors, resulting in different domain architectures, reaction mechanisms and active site properties. In this review, we will discuss for each family of serine/threonine protein phosphatases, their involvement in biological process and corresponding strategies for small chemical intervention. Recent advances in modern drug discovery technologies have markedly facilitated the identification of selective inhibitors for some members of the phosphatase family. Furthermore, the rapid growth in knowledge about structure-activity relationships related to possible new drug targets has aided the discovery of natural product inhibitors for phosphatase family. This review summarizes the current state of investigation of the small molecules that regulate the function of serine/threonine phosphatases, the challenges presented and also strategies to overcome these obstacles.

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Flexibility in the PP1:spinophilin holoenzyme

Cited by 22 publications

References 20 publications

Identification of a Plasmodium falciparum inhibitor‐2 motif involved in the binding and regulation activity of protein phosphatase type 1

Identification of a Plasmodium falciparum inhibitor‐2 motif involved in the binding and regulation activity of protein phosphatase type 1

Regulation of protein phosphatase 1 by intrinsically disordered proteins

Viewing serine/threonine protein phosphatases through the eyes of drug designers

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