scholarly journals Regulation of the phosphatase PP2B by protein–protein interactions

2016 ◽  
Vol 44 (5) ◽  
pp. 1313-1319 ◽  
Author(s):  
Patrick J. Nygren ◽  
John D. Scott
Keyword(s):  
Protein Interactions ◽  
Protein Phosphatase ◽  
Therapeutic Benefit ◽  
Protein Protein Interactions ◽  
Binding Motifs ◽  
Protein Substrates ◽  
Protein Phosphatase 2B ◽  
Anchoring Protein ◽  
Protein Dephosphorylation

Protein dephosphorylation is important for regulating cellular signaling in a variety of contexts. Protein phosphatase-2B (PP2B), or calcineurin, is a widely expressed serine/threonine phosphatase that acts on a large cross section of potential protein substrates when activated by increased levels of intracellular calcium in concert with calmodulin. PxIxIT and LxVP targeting motifs are important for maintaining specificity in response to elevated calcium. In the present study, we describe the mechanism of PP2B activation, discuss its targeting by conserved binding motifs and review recent advances in the understanding of an A-kinase anchoring protein 79/PP2B/protein kinase A complex's role in synaptic long-term depression. Finally, we discuss potential for targeting PP2B anchoring motifs for therapeutic benefit.

scholarly journals Multiple Interactions within the AKAP220 Signaling Complex Contribute to Protein Phosphatase 1 Regulation

2001 ◽  
Vol 276 (15) ◽  
pp. 12128-12134 ◽  
Author(s):  
Robynn V. Schillace ◽  
James W. Voltz ◽  
Alistair T. R. Sim ◽  
Shirish Shenolikar ◽  
John D. Scott
Keyword(s):  
Intermolecular Interactions ◽  
Protein Interactions ◽  
Protein Phosphatase ◽  
Competitive Inhibitor ◽  
Regulatory Subunit ◽  
Protein Protein Interactions ◽  
Signaling Complex ◽  
Activity Measurements ◽  
Anchoring Protein ◽  
Pka Regulatory Subunit

The phosphorylation status of cellular proteins is controlled by the opposing actions of protein kinases and phosphatases. Compartmentalization of these enzymes is critical for spatial and temporal control of these phosphorylation/dephosphorylation events. We previously reported that a 220-kDa A-kinase anchoring protein (AKAP220) coordinates the location of the cAMP-dependent protein kinase (PKA) and the type 1 protein phosphatase catalytic subunit (PP1c) (Schillace, R. V., and Scott, J. D. (1999)Curr. Biol.9, 321–324). We now demonstrate that an AKAP220 fragment is a competitive inhibitor of PP1c activity (Ki= 2.9 ± 0.7 μm). Mapping studies and activity measurements indicate that several protein-protein interactions act synergistically to inhibit PP1. A consensus targeting motif, between residues 1195 and 1198 (Lys-Val-Gln-Phe), binds but does not affect enzyme activity, whereas determinants between residues 1711 and 1901 inhibit the phosphatase. Analysis of truncated PP1c and chimeric PP1/2A catalytic subunits suggests that AKAP220 inhibits the phosphatase in a manner distinct from all known PP1 inhibitors and toxins. Intermolecular interactions within the AKAP220 signaling complex further contribute to PP1 inhibition as addition of the PKA regulatory subunit (RII) enhances phosphatase inhibition. These experiments indicate that regulation of PP1 activity by AKAP220 involves a complex network of intra- and intermolecular interactions.

scholarly journals ArabidopsisImmunophilin-like TWD1 Functionally Interacts with Vacuolar ABC Transporters

2004 ◽  
Vol 15 (7) ◽  
pp. 3393-3405 ◽  
Author(s):  
Markus Geisler ◽  
Marjolaine Girin ◽  
Sabine Brandt ◽  
Vincent Vincenzetti ◽  
Sonia Plaza ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Abc Transporters ◽  
Loss Of Function ◽  
Protein Protein Interactions ◽  
Binding Motifs ◽  
Calmodulin Binding ◽  
C Terminus ◽  
Domain Mapping ◽  
Tetratricopeptide Repeat Domain

Previously, the immunophilin-like protein TWD1 from Arabidopsis has been demonstrated to interact with the ABC transporters AtPGP1 and its closest homologue, AtPGP19. Physiological and biochemical investigation of pgp1/pgp19 and of twd1 plants suggested a regulatory role of TWD1 on AtPGP1/AtPGP19 transport activities. To further understand the dramatic pleiotropic phenotype that is caused by loss-of-function mutation of the TWD1 gene, we were interested in other TWD1 interacting proteins. AtMRP1, a multidrug resistance-associated (MRP/ABCC)-like ABC transporter, has been isolated in a yeast two-hybrid screen. We demonstrate molecular interaction between TWD1 and ABC transporters AtMRP1 and its closest homologue, AtMRP2. Unlike AtPGP1, AtMRP1 binds to the C-terminal tetratricopeptide repeat domain of TWD1, which is well known to mediate protein-protein interactions. Domain mapping proved that TWD1 binds to a motif of AtMRP1 that resembles calmodulin-binding motifs; and calmodulin binding to the C-terminus of MRP1 was verified. By membrane fractionation and GFP-tagging, we localized AtMRP1 to the central vacuolar membrane and the TWD1-AtMRP1 complex was verified in vivo by coimmunoprecipitation. We were able to demonstrate that TWD1 binds to isolated vacuoles and has a significant impact on the uptake of metolachlor-GS and estradiol-β-glucuronide, well-known substrates of vacuolar transporters AtMRP1 and AtMRP2.

scholarly journals GluR2 protein-protein interactions and the regulation of AMPA receptors during synaptic plasticity

2003 ◽  
Vol 358 (1432) ◽  
pp. 715-720 ◽  
Author(s):  
Fabrice Duprat ◽  
Michael Daw ◽  
Wonil Lim ◽  
Graham Collingridge ◽  
John Isaac
Keyword(s):  
Synaptic Plasticity ◽  
Ampa Receptor ◽  
Protein Interactions ◽  
Ampa Receptors ◽  
Long Term Potentiation ◽  
Synaptic Proteins ◽  
Mammalian Brain ◽  
Protein Protein Interactions ◽  
Term Potentiation

AMPA-type glutamate receptors mediate most fast excitatory synaptic transmissions in the mammalian brain. They are critically involved in the expression of long-term potentiation and long-term depression, forms of synaptic plasticity that are thought to underlie learning and memory. A number of synaptic proteins have been identified that interact with the intracellular C-termini of AMPA receptor subunits. Here, we review recent studies and present new experimental data on the roles of these interacting proteins in regulating the AMPA receptor function during basal synaptic transmission and plasticity.

scholarly journals Expression attenuation as a mechanism of robustness against gene duplication

2021 ◽  
Vol 118 (6) ◽  
pp. e2014345118
Author(s):  
Diana Ascencio ◽  
Guillaume Diss ◽  
Isabelle Gagnon-Arsenault ◽  
Alexandre K. Dubé ◽  
Alexander DeLuna ◽  
...  
Keyword(s):  
Gene Duplication ◽  
Protein Interactions ◽  
Protein Complexes ◽  
Phenotypic Diversity ◽  
26S Proteasome ◽  
Gene Duplications ◽  
Protein Protein Interactions ◽  
Individual Gene ◽  
The Impact

Gene duplication is ubiquitous and a major driver of phenotypic diversity across the tree of life, but its immediate consequences are not fully understood. Deleterious effects would decrease the probability of retention of duplicates and prevent their contribution to long-term evolution. One possible detrimental effect of duplication is the perturbation of the stoichiometry of protein complexes. Here, we measured the fitness effects of the duplication of 899 essential genes in the budding yeast using high-resolution competition assays. At least 10% of genes caused a fitness disadvantage when duplicated. Intriguingly, the duplication of most protein complex subunits had small to nondetectable effects on fitness, with few exceptions. We selected four complexes with subunits that had an impact on fitness when duplicated and measured the impact of individual gene duplications on their protein–protein interactions. We found that very few duplications affect both fitness and interactions. Furthermore, large complexes such as the 26S proteasome are protected from gene duplication by attenuation of protein abundance. Regulatory mechanisms that maintain the stoichiometric balance of protein complexes may protect from the immediate effects of gene duplication. Our results show that a better understanding of protein regulation and assembly in complexes is required for the refinement of current models of gene duplication.

scholarly journals Inhibition of β-catenin–TCF1 interaction delays differentiation of mouse embryonic stem cells

2015 ◽  
Vol 211 (1) ◽  
pp. 39-51 ◽  
Author(s):  
Sujash S. Chatterjee ◽  
Abil Saj ◽  
Tenzin Gocha ◽  
Matthew Murphy ◽  
Foster C. Gonsalves ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Cell Fate ◽  
Protein Interactions ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cells ◽  
Protein Protein Interactions ◽  
Nanog Expression ◽  
Context Specific

The ability of mouse embryonic stem cells (mESCs) to self-renew or differentiate into various cell lineages is regulated by signaling pathways and a core pluripotency transcriptional network (PTN) comprising Nanog, Oct4, and Sox2. The Wnt/β-catenin pathway promotes pluripotency by alleviating T cell factor TCF3-mediated repression of the PTN. However, it has remained unclear how β-catenin’s function as a transcriptional activator with TCF1 influences mESC fate. Here, we show that TCF1-mediated transcription is up-regulated in differentiating mESCs and that chemical inhibition of β-catenin/TCF1 interaction improves long-term self-renewal and enhances functional pluripotency. Genetic loss of TCF1 inhibited differentiation by delaying exit from pluripotency and conferred a transcriptional profile strikingly reminiscent of self-renewing mESCs with high Nanog expression. Together, our data suggest that β-catenin’s function in regulating mESCs is highly context specific and that its interaction with TCF1 promotes differentiation, further highlighting the need for understanding how its individual protein–protein interactions drive stem cell fate.

Modulating the Bcl-2 Family of Apoptosis Suppressors for Potential Therapeutic Benefit in Cancer

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 226-230 ◽  
Author(s):  
Gordon C. Shore ◽  
Jean Viallet
Keyword(s):  
Protein Interactions ◽  
Therapeutic Benefit ◽  
Protein Protein Interactions ◽  
Cancer Treatments ◽  
The Family ◽  
Challenges And Opportunities ◽  
Apoptosis Pathways ◽  
Current Therapies ◽  
Cellular Oncogenes ◽  
Potential Therapeutic Benefit

Abstract Members of the BCL-2 family of proteins regulate and execute many cell intrinsic apoptosis pathways, including those arising from dysregulated expression of cellular oncogenes. Since pro-survival members of the family are often strongly elevated in diverse cancers, with the potential to confer resistance to both endogenous cell death stimuli and many cancer treatments, there has been intense interest to develop strategies to therapeutically modulate their activity. Although encouraging genetic and pharmacological preclinical proof of concept has been obtained, the challenge for clinical development will be to devise strategies that address the fact that multiple pro-survival members are typically up-regulated in a given cancer and the family operates primarily through protein-protein interactions. Moreover, since several current therapies themselves are known to stimulate the levels of one or more family members, there will be additional challenges (and opportunities) in exploiting this target in the clinic. In this review, we describe the rationale for targeting the BCL-2 family of apoptosis suppressors in cancer and the progress that has been made in modulating the family by small molecule antagonists.

scholarly journals Expression attenuation as a mechanism of robustness to gene duplication in protein complexes

2020 ◽  
Author(s):  
Diana Ascencio ◽  
Guillaume Diss ◽  
Isabelle Gagnon-Arsenault ◽  
Alexandre K Dubé ◽  
Alexander DeLuna ◽  
...  
Keyword(s):  
Gene Duplication ◽  
Protein Interactions ◽  
Protein Complexes ◽  
Phenotypic Diversity ◽  
26S Proteasome ◽  
Gene Duplications ◽  
Protein Protein Interactions ◽  
Individual Gene ◽  
The Impact

AbstractGene duplication is ubiquitous and a major driver of phenotypic diversity across the tree of life, but its immediate consequences are not fully understood. Deleterious effects would decrease the probability of retention of duplicates and prevent their contribution to long term evolution. One possible detrimental effect of duplication is the perturbation of the stoichiometry of protein complexes. Here, we measured the fitness effects of the duplication of 899 essential genes in the budding yeast using high-resolution competition assays. At least ten percent of genes caused a fitness disadvantage when duplicated. Intriguingly, the duplication of most protein complex subunits had small to non-detectable effects on fitness, with few exceptions. We selected four complexes with subunits that had an impact on fitness when duplicated and measured the impact of individual gene duplications on their protein-protein interactions. We found that very few duplications affect both fitness and interactions. Furthermore, large complexes such as the 26S proteasome are protected from gene duplication by attenuation of protein abundance. Regulatory mechanisms that maintain the stoichiometric balance of protein complexes may protect from the immediate effects of gene duplication. Our results show that a better understanding of protein regulation and assembly in complexes is required for the refinement of current models of gene duplication.

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