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Search results for: Protein Phosphatase 1 subunit GM

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#32784920   2020/08/09 To Up

The Evolution of Duplicated Genes of the Cpi-17/Phi-1 () Family of Protein Phosphatase 1 Inhibitors in Teleosts.

The Cpi-17 () gene family is an evolutionarily conserved, vertebrate specific group of protein phosphatase 1 (PP1) inhibitors. When phosphorylated, Cpi-17 is a potent inhibitor of myosin phosphatase (MP), a holoenzyme complex of the regulatory subunit Mypt1 and the catalytic subunit PP1. Myosin phosphatase dephosphorylates the regulatory myosin light chain (Mlc2) and promotes actomyosin relaxation, which in turn, regulates numerous cellular processes including smooth muscle contraction, cytokinesis, cell motility, and tumor cell invasion. We analyzed zebrafish homologs of the Cpi-17 family, to better understand the mechanisms of myosin phosphatase regulation. We found single homologs of both Kepi () and Gbpi () in silico, but we detected no expression of these genes during early embryonic development. Cpi-17 () and Phi-1 () each had two duplicate paralogs, ( and ) and ( and ), which were each expressed during early development. The spatial expression pattern of these genes has diverged, with and expressed primarily in smooth muscle and skeletal muscle, respectively, while and are primarily expressed in neural tissue. We observed that, in in vitro and heterologous cellular systems, the Cpi-17 paralogs both acted as potent myosin phosphatase inhibitors, and were indistinguishable from one another. In contrast, the two Phi-1 paralogs displayed weak myosin phosphatase inhibitory activity in vitro, and did not alter myosin phosphorylation in cells. Through deletion and chimeric analysis, we identified that the difference in specificity for myosin phosphatase between Cpi-17 and Phi-1 was encoded by the highly conserved PHIN (phosphatase holoenzyme inhibitory) domain, and not the more divergent N- and C- termini. We also showed that either Cpi-17 paralog can rescue the knockdown phenotype, but neither Phi-1 paralog could do so. Thus, we provide new evidence about the biochemical and developmental distinctions of the zebrafish Cpi-17 protein family.
Irene Lang, Guneet Virk, Dale C Zheng, Jason Young, Michael J Nguyen, Rojin Amiri, Michelle Fong, Alisa Arata, Katia S Chadaideh, Susan Walsh, Douglas C Weiser

1920 related Products with: The Evolution of Duplicated Genes of the Cpi-17/Phi-1 () Family of Protein Phosphatase 1 Inhibitors in Teleosts.

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#31883643   2019/12/26 To Up

Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations.

In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development.
Joel J Hughes, Ebba Alkhunaizi, Paul Kruszka, Louise C Pyle, Dorothy K Grange, Seth I Berger, Katelyn K Payne, Diane Masser-Frye, Tommy Hu, Michelle R Christie, Nancy J Clegg, Joshua L Everson, Ariel F Martinez, Laurence E Walsh, Emma Bedoukian, Marilyn C Jones, Catharine Jean Harris, Korbinian M Riedhammer, Daniela Choukair, Patricia Y Fechner, Meilan M Rutter, Sophia B Hufnagel, Maian Roifman, Gad B Kletter, Emmanuele Delot, Eric Vilain, Robert J Lipinski, Chad M Vezina, Maximilian Muenke, David Chitayat

2604 related Products with: Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations.

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#31710605   2019/11/11 To Up

SUR-8 interacts with PP1-87B to stabilize PERIOD and regulate circadian rhythms in Drosophila.

Circadian rhythms are generated by endogenous pacemakers that rely on transcriptional-translational feedback mechanisms conserved among species. In Drosophila, the stability of a key pacemaker protein PERIOD (PER) is tightly controlled by changes in phosphorylation status. A number of molecular players have been implicated in PER destabilization by promoting PER progressive phosphorylation. On the other hand, there have been few reports describing mechanisms that stabilize PER by delaying PER hyperphosphorylation. Here we report that the protein Suppressor of Ras (SUR-8) regulates circadian locomotor rhythms by stabilizing PER. Depletion of SUR-8 from circadian neurons lengthened the circadian period by about 2 hours and decreased PER abundance, whereas its overexpression led to arrhythmia and an increase in PER. Specifically SUR-8 promotes the stability of PER through phosphorylation regulation. Interestingly, downregulation of the protein phosphatase 1 catalytic subunit PP1-87B recapitulated the phenotypes of SUR-8 depletion. We found that SUR-8 facilitates interactions between PP1-87B and PER. Depletion of SUR-8 decreased the interaction of PER and PP1-87B, which supports the role of SUR-8 as a scaffold protein. Interestingly, the interaction between SUR-8 and PER is temporally regulated: SUR-8 has more binding to PER at night than morning. Thus, our results indicate that SUR-8 interacts with PP1-87B to control PER stability to regulate circadian rhythms.
Yongbo Xue, Joanna C Chiu, Yong Zhang

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#31548429   2019/09/23 To Up

SDS22 selectively recognizes and traps metal-deficient inactive PP1.

The metalloenzyme protein phosphatase 1 (PP1), which is responsible for ≥50% of all dephosphorylation reactions, is regulated by scores of regulatory proteins, including the highly conserved SDS22 protein. SDS22 has numerous diverse functions, surprisingly acting as both a PP1 inhibitor and as an activator. Here, we integrate cellular, biophysical, and crystallographic studies to address this conundrum. We discovered that SDS22 selectively binds a unique conformation of PP1 that contains a single metal (M2) at its active site, i.e., SDS22 traps metal-deficient inactive PP1. Furthermore, we showed that SDS22 dissociation is accompanied by a second metal (M1) being loaded into PP1, as free metal cannot dissociate the complex and M1-deficient mutants remain constitutively trapped by SDS22. Together, our findings reveal that M1 metal loading and loss are essential for PP1 regulation in cells, which has broad implications for PP1 maturation, activity, and holoenzyme subunit exchange.
Meng S Choy, Thomas M Moon, Rini Ravindran, Johnny A Bray, Lucy C Robinson, Tara L Archuleta, Wuxian Shi, Wolfgang Peti, Kelly Tatchell, Rebecca Page

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#31395656   2019/08/08 To Up

Dephosphorylation activates the interferon-stimulated Schlafen family member 11 in the DNA damage response.

Human Schlafen 11 () is an interferon-stimulated gene (ISG) that we previously have demonstrated to ablate translation of HIV proteins based on the virus's distinct codon preference. Additionally, lack of SLFN11 expression has been linked to the resistance of cancer cells to DNA-damaging agents (DDAs). We recently resolved the underlying mechanism, finding that it involves SLFN11-mediated cleavage of select tRNAs predominantly employed in the translation of the ATR and ATM Ser/Thr kinases, thereby establishing SLFN11 as a novel tRNA endonuclease. Even though SLFN11 is thus involved in two of the most prominent diseases of our time, cancer and HIV infection, its regulation remained thus far unresolved. Using MS and bioinformatics-based approaches combined with site-directed mutagenesis, we show here that SLFN11 is phosphorylated at three different sites, which requires dephosphorylation for SLFN11 to become fully functionally active. Furthermore, we identified protein phosphatase 1 catalytic subunit γ (PPP1CC) as the upstream enzyme whose activity is required for SLFN11 to cleave tRNAs and thereby act as a selective translational inhibitor. In summary, our work has identified both the mechanism of SLFN11 activation and PPP1CC as the enzyme responsible for its activation. Our findings open up future studies of the PPP1CC subunit(s) involved in SLFN11 activation and the putative kinase(s) that inactivates SLFN11.
Dane Malone, Rea M Lardelli, Manqing Li, Michael David

2677 related Products with: Dephosphorylation activates the interferon-stimulated Schlafen family member 11 in the DNA damage response.

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#31291571   // To Up

NMDAR-Activated PP1 Dephosphorylates GluN2B to Modulate NMDAR Synaptic Content.

In mature neurons, postsynaptic N-methyl-D-aspartate receptors (NMDARs) are segregated into two populations, synaptic and extrasynaptic, which differ in localization, function, and associated intracellular cascades. These two pools are connected via lateral diffusion, and receptor exchange between them modulates synaptic NMDAR content. Here, we identify the phosphorylation of the PDZ-ligand of the GluN2B subunit of NMDARs (at S1480) as a critical determinant in dynamically controlling NMDAR synaptic content. We find that phosphorylation of GluN2B at S1480 maintains NMDARs at extrasynaptic membranes as part of a protein complex containing protein phosphatase 1 (PP1). Global activation of NMDARs leads to the activation of PP1, which mediates dephosphorylation of GluN2B at S1480 to promote an increase in synaptic NMDAR content. Thus, PP1-mediated dephosphorylation of the GluN2B PDZ-ligand modulates the synaptic expression of NMDARs in mature neurons in an activity-dependent manner, a process with profound consequences for synaptic and structural plasticity, metaplasticity, and synaptic neurotransmission.
Andrew M Chiu, Jiejie Wang, Michael P Fiske, Pavla Hubalkova, Levi Barse, John A Gray, Antonio Sanz-Clemente

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#31087825   2019/05/07 To Up

Predicting Worsening Suicidal Ideation With Clinical Features and Peripheral Expression of Messenger RNA and MicroRNA During Antidepressant Treatment.

To investigate how the combination of clinical and molecular biomarkers can predict worsening of suicidal ideation during antidepressant treatment.
Raoul Belzeaux, Laura M Fiori, Juan Pablo Lopez, Mohamed Boucekine, Laurent Boyer, Pierre Blier, Faranak Farzan, Benicio N Frey, Peter Giacobbe, Raymond W Lam, Francesco Leri, Glenda M MacQueen, Roumen Milev, Daniel J Müller, Sagar V Parikh, Susan Rotzinger, Claudio N Soares, Rudolf Uher, Jane A Foster, Sidney H Kennedy, Gustavo Turecki

2333 related Products with: Predicting Worsening Suicidal Ideation With Clinical Features and Peripheral Expression of Messenger RNA and MicroRNA During Antidepressant Treatment.

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#30770806   2019/02/15 To Up

ASPP proteins discriminate between PP1 catalytic subunits through their SH3 domain and the PP1 C-tail.

Serine/threonine phosphatases such as PP1 lack substrate specificity and associate with a large array of targeting subunits to achieve the requisite selectivity. The tumour suppressor ASPP (apoptosis-stimulating protein of p53) proteins associate with PP1 catalytic subunits and are implicated in multiple functions from transcriptional regulation to cell junction remodelling. Here we show that Drosophila ASPP is part of a multiprotein PP1 complex and that PP1 association is necessary for several in vivo functions of Drosophila ASPP. We solve the crystal structure of the human ASPP2/PP1 complex and show that ASPP2 recruits PP1 using both its canonical RVxF motif, which binds the PP1 catalytic domain, and its SH3 domain, which engages the PP1 C-terminal tail. The ASPP2 SH3 domain can discriminate between PP1 isoforms using an acidic specificity pocket in the n-Src domain, providing an exquisite mechanism where multiple motifs are used combinatorially to tune binding affinity to PP1.
M Teresa Bertran, Stéphane Mouilleron, Yanxiang Zhou, Rakhi Bajaj, Federico Uliana, Ganesan Senthil Kumar, Audrey van Drogen, Rebecca Lee, Jennifer J Banerjee, Simon Hauri, Nicola O'Reilly, Matthias Gstaiger, Rebecca Page, Wolfgang Peti, Nicolas Tapon

2973 related Products with: ASPP proteins discriminate between PP1 catalytic subunits through their SH3 domain and the PP1 C-tail.

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#30661852   2019/01/17 To Up

Structure-Guided Exploration of SDS22 Interactions with Protein Phosphatase PP1 and the Splicing Factor BCLAF1.

SDS22 is an ancient regulator of protein phosphatase-1 (PP1). Our crystal structure of SDS22 shows that its twelve leucine-rich repeats adopt a banana-shaped fold that is shielded from solvent by capping domains at its extremities. Subsequent modeling and biochemical studies revealed that the concave side of SDS22 likely interacts with PP1 helices α5 and α6, which are distal from the binding sites of many previously described PP1 interactors. Accordingly, we found that SDS22 acts as a "third" subunit of multiple PP1 holoenzymes. The crystal structure of SDS22 also revealed a large basic surface patch that enables binding of a phosphorylated form of splicing factor BCLAF1. Taken together, our data provide insights into the formation of PP1:SDS22 and the recruitment of additional interaction proteins, such as BCLAF1.
Ewald Heroes, Gerd Van der Hoeven, Meng S Choy, Javier Del Pino Garcia, Mónica Ferreira, Mieke Nys, Rita Derua, Monique Beullens, Chris Ulens, Wolfgang Peti, Luc Van Meervelt, Rebecca Page, Mathieu Bollen

2508 related Products with: Structure-Guided Exploration of SDS22 Interactions with Protein Phosphatase PP1 and the Splicing Factor BCLAF1.

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#30443599   2018/11/14 To Up

Identification of the substrate recruitment mechanism of the muscle glycogen protein phosphatase 1 holoenzyme.

Glycogen is the primary storage form of glucose. Glycogen synthesis and breakdown are tightly controlled by glycogen synthase (GYS) and phosphorylase, respectively. The enzyme responsible for dephosphorylating GYS and phosphorylase, which results in their activation (GYS) or inactivation (phosphorylase) to robustly stimulate glycogen synthesis, is protein phosphatase 1 (PP1). However, our understanding of how PP1 recruits these substrates is limited. Here, we show how PP1, together with its muscle glycogen-targeting (G) regulatory subunit, recruits and selectively dephosphorylates its substrates. Our molecular data reveal that the G carbohydrate binding module (G), which is amino-terminal to the G PP1 binding domain, has a dual function in directing PP1 substrate specificity: It either directly recruits substrates (i.e., GYS) or recruits them indirectly by localization (via glycogen for phosphorylase). Our data provide the molecular basis for PP1 regulation by G and reveal how PP1-mediated dephosphorylation is driven by scaffolding-based substrate recruitment.
Ganesan Senthil Kumar, Meng S Choy, Dorothy M Koveal, Michael K Lorinsky, Scott P Lyons, Arminja N Kettenbach, Rebecca Page, Wolfgang Peti

1504 related Products with: Identification of the substrate recruitment mechanism of the muscle glycogen protein phosphatase 1 holoenzyme.

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