scholarly journals SIRT2 deacetylase regulates the activity of GSK3 isoforms independent of inhibitory phosphorylation

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Mohsen Sarikhani ◽  
Sneha Mishra ◽  
Sangeeta Maity ◽  
Chaithanya Kotyada ◽  
Donald Wolfgeher ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Serine Phosphorylation ◽  
Glycogen Synthase Kinase 3 ◽  
Lysine Acetylation ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Dynamics Simulations ◽  
And Function ◽  
Reduced Activity ◽  
Deficient Mice

Glycogen synthase kinase 3 (GSK3) is a critical regulator of diverse cellular functions involved in the maintenance of structure and function. Enzymatic activity of GSK3 is inhibited by N-terminal serine phosphorylation. However, alternate post-translational mechanism(s) responsible for GSK3 inactivation are not characterized. Here, we report that GSK3α and GSK3β are acetylated at Lys246 and Lys183, respectively. Molecular modeling and/or molecular dynamics simulations indicate that acetylation of GSK3 isoforms would hinder both the adenosine binding and prevent stable interactions of the negatively charged phosphates. We found that SIRT2 deacetylates GSK3β, and thus enhances its binding to ATP. Interestingly, the reduced activity of GSK3β is associated with lysine acetylation, but not with phosphorylation at Ser9 in hearts of SIRT2-deficient mice. Moreover, GSK3 is required for the anti-hypertrophic function of SIRT2 in cardiomyocytes. Overall, our study identified lysine acetylation as a novel post-translational modification regulating GSK3 activity.

scholarly journals Identification of a novel selective and potent inhibitor of glycogen synthase kinase-3

2019 ◽  
Vol 317 (6) ◽  
pp. C1289-C1303 ◽  
Author(s):  
Mahboubeh S. Noori ◽  
Pooja M. Bhatt ◽  
Maria C. Courreges ◽  
Davoud Ghazanfari ◽  
Chaz Cuckler ◽  
...  
Keyword(s):  
Design Space ◽  
Potent Inhibitor ◽  
Glycogen Synthase ◽  
Selective Inhibition ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Cellular Functions ◽  
Starting Point ◽  
Potential Therapeutics

Glycogen synthase kinase-3 (GSK-3) is a multitasking protein kinase that regulates numerous critical cellular functions. Not surprisingly, elevated GSK-3 activity has been implicated in a host of diseases including pathological inflammation, diabetes, cancer, arthritis, asthma, bipolar disorder, and Alzheimer’s. Therefore, reagents that inhibit GSK-3 activity provide a means to investigate the role of GSK-3 in cellular physiology and pathophysiology and could become valuable therapeutics. Finding a potent inhibitor of GSK-3 that can selectively target this kinase, among over 500 protein kinases in the human genome, is a significant challenge. Thus there remains a critical need for the identification of selective inhibitors of GSK-3. In this work, we introduce a novel small organic compound, namely COB-187, which exhibits potent and highly selective inhibition of GSK-3. Specifically, this study 1) utilized a molecular screen of 414 kinase assays, representing 404 unique kinases, to reveal that COB-187 is a highly potent and selective inhibitor of GSK-3; 2) utilized a cellular assay to reveal that COB-187 decreases the phosphorylation of canonical GSK-3 substrates indicating that COB-187 inhibits cellular GSK-3 activity; and 3) reveals that a close isomer of COB-187 is also a selective and potent inhibitor of GSK-3. Taken together, these results demonstrate that we have discovered a region of chemical design space that contains novel GSK-3 inhibitors. These inhibitors will help to elucidate the intricate function of GSK-3 and can serve as a starting point for the development of potential therapeutics for diseases that involve aberrant GSK-3 activity.

Glycogen synthase kinase-3 as a key regulator of cognitive function

2020 ◽  
Vol 52 (3) ◽  
pp. 219-230 ◽  
Author(s):  
Xuhong Fan ◽  
Zhenyu Zhao ◽  
Deming Wang ◽  
Ji Xiao
Keyword(s):  
Cognitive Function ◽  
Neural Plasticity ◽  
Glycogen Synthase ◽  
Current Knowledge ◽  
Cell Structure ◽  
Glycogen Synthesis ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Cellular Functions ◽  
Related Disease

Abstract Glycogen synthase kinase-3 (GSK-3) is a highly conserved and multifunctional serine/threonine protein kinase widely distributed in eukaryotic cells. GSK-3 is originally thought to be an enzyme that regulates glycogen synthesis. It was subsequently found that GSK-3 influences many critical cellular functions, such as cell structure, neural plasticity, gene expression, and neuronal survival. Recently, GSK-3 has been found to be associated with cognition, and its dysregulation leads to cognitive impairments in many diseases, including Alzheimer’s disease, diabetes, depression, Parkinson’s disease, and others. In this review, we summarized the current knowledge about the structure of GSK-3, the regulation of GSK-3 activity, and its role in cognitive function and cognitive-related disease.

scholarly journals An atlas of Arabidopsis protein S-Acylation reveals its widespread role in plant cell organisation of and function

2020 ◽  
Author(s):  
Manoj Kumar ◽  
Paul Carr ◽  
Simon Turner
Keyword(s):  
Sequence Similarity ◽  
Protein S ◽  
Cysteine Residue ◽  
Cellulose Synthesis ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Ring Type ◽  
Arabidopsis Proteome ◽  
Arabidopsis Protein ◽  
And Function

AbstractS-acylation is the addition of a fatty acid to a cysteine residue of a protein. While this modification may profoundly alter protein behaviour, its effects on the function of plant proteins remains poorly characterised, largely as a result to the lack of basic information regarding which proteins are S-acylated and where in the proteins the modification occurs. In order to address this gap in our knowledge, we have performed a comprehensive analysis of plant protein S-acylation from 6 separate tissues. In our highest confidence group, we identified 5185 cysteines modified by S-acylation, which were located in 4891 unique peptides from 2643 different proteins. This represents around 9% of the entire Arabidopsis proteome and suggests an important role for S-acylation in many essential cellular functions including trafficking, signalling and metabolism. To illustrate the potential of this dataset, we focus on cellulose synthesis and confirm for the first time the S-acylation of all proteins known to be involved in cellulose synthesis and trafficking of the cellulose synthase complex. In the secondary cell walls, cellulose synthesis requires three different catalytic subunits (CESA4, CESA7 and CESA8) that all exhibit striking sequence similarity. While all three proteins have been widely predicted to possess a RING-type zinc finger at their N-terminus, for CESA4 and CESA8, we find evidence for S-acylation of cysteines in this region that is incompatible with any role in coordinating metal ions. We show that while CESA7 may possess a RING type domain, the same region of CESA4 and CESA8 appear to have evolved a very different structure. Together, the data suggests this study represents an atlas of S-acylation in Arabidopsis that will facilitate the broader study of this elusive post-translational modification in plants as well as demonstrates the importance of undertaking further work in this area.

scholarly journals Mammalian Sir2 Homolog SIRT3 Regulates Global Mitochondrial Lysine Acetylation

2007 ◽  
Vol 27 (24) ◽  
pp. 8807-8814 ◽  
Author(s):  
David B. Lombard ◽  
Frederick W. Alt ◽  
Hwei-Ling Cheng ◽  
Jakob Bunkenborg ◽  
Ryan S. Streeper ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mitochondrial Protein ◽  
Mitochondrial Proteins ◽  
Lysine Acetylation ◽  
Biochemical Phenotype ◽  
Adaptive Thermogenesis ◽  
Cell Culture Systems ◽  
And Function ◽  
Deficient Mice

ABSTRACT Homologs of the Saccharomyces cerevisiae Sir2 protein, sirtuins, promote longevity in many organisms. Studies of the sirtuin SIRT3 have so far been limited to cell culture systems. Here, we investigate the localization and function of SIRT3 in vivo. We show that endogenous mouse SIRT3 is a soluble mitochondrial protein. To address the function and relevance of SIRT3 in the regulation of energy metabolism, we generated and phenotypically characterized SIRT3 knockout mice. SIRT3-deficient animals exhibit striking mitochondrial protein hyperacetylation, suggesting that SIRT3 is a major mitochondrial deacetylase. In contrast, no mitochondrial hyperacetylation was detectable in mice lacking the two other mitochondrial sirtuins, SIRT4 and SIRT5. Surprisingly, despite this biochemical phenotype, SIRT3-deficient mice are metabolically unremarkable under basal conditions and show normal adaptive thermogenesis, a process previously suggested to involve SIRT3. Overall, our results extend the recent finding of lysine acetylation of mitochondrial proteins and demonstrate that SIRT3 has evolved to control reversible lysine acetylation in this organelle.

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