scholarly journals N-terminal phosphorylation regulates the activity of Glycogen Synthase Kinase 3 from Plasmodium falciparum

2022 ◽  
Author(s):  
Samuel Pazicky ◽  
Arne Alder ◽  
Haydyn Mertens ◽  
Dmitri I. Svergun ◽  
Tim Gilberger ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Conformational Changes ◽  
Glycogen Synthase ◽  
New Drugs ◽  
Glycogen Synthase Kinase ◽  
Scattering Data ◽  
Glycogen Synthase Kinase 3 ◽  
X Ray ◽  
X Ray Scattering ◽  
Novel Targets

As the decline of malaria cases stalled over the last five years, novel targets in Plasmodium falciparum are necessary for the development of new drugs. Glycogen Synthase Kinase (PfGSK3) has been identified as a potential target, since its selective inhibitors were shown to disrupt the parasite's life cycle. In the uncanonical N‑terminal region of the parasite enzyme, we identified several autophosphorylation sites and probed their role in activity regulation of PfGSK3. By combining molecular modeling with experimental small-angle X-ray scattering data, we show that increased PfGSK3 activity is promoted by conformational changes in the PfGSK3 N‑terminus, triggered by N‑terminal phosphorylation. Our work provides novel insights into the structure and regulation of the malarial PfGSK3.

scholarly journals N-terminal phosphorylation regulates the activity of Glycogen Synthase Kinase 3 from Plasmodium falciparum

2021 ◽  
Author(s):  
Samuel Pazicky ◽  
Arne Alder ◽  
Haydyn Mertens ◽  
D. I. Svergun ◽  
Tim Gilberger ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Conformational Changes ◽  
Glycogen Synthase ◽  
New Drugs ◽  
Glycogen Synthase Kinase ◽  
Scattering Data ◽  
Glycogen Synthase Kinase 3 ◽  
X Ray ◽  
X Ray Scattering

As the decline of malaria cases stalled over the last five years, novel targets in Plasmodium falciparum are necessary for the development of new drugs. Glycogen Synthase Kinase (PfGSK3) has been identified as a potential target, since its selective inhibitors were shown to disrupt the parasite`s life cycle. Here, we show that PfGSK3 exhibits autophosphorylation, leading to an extensive phosphorylation both in vitro and in the parasite. In the uncanonical N-terminal region of the parasite enzyme, we identified several autophosphorylation sites that regulate the activity of PfGSK3. By combining molecular modeling with experimental small-angle X-ray scattering data, we show that increased PfGSK3 activity is promoted by conformational changes in the PfGSK3 N-terminus, triggered by N-terminal phosphorylation. Our work provides novel insights into the structure and regulation of the malarial PfGSK3.

3,6-Diamino-4-(2-halophenyl)-2-benzoylthieno[2,3-b]pyridine-5-carbonitriles Are Selective Inhibitors of Plasmodium falciparum Glycogen Synthase Kinase-3

2012 ◽  
Vol 56 (1) ◽  
pp. 264-275 ◽  
Author(s):  
Wiebke Fugel ◽  
Anselm Erich Oberholzer ◽  
Bernhard Gschloessl ◽  
Ron Dzikowski ◽  
Narkiss Pressburger ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Selective Inhibitors

Multifunctional Ligands with Glycogen Synthase Kinase 3 Inhibitory Activity as a New Direction in Drug Research for Alzheimer’s Disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Agnieszka Jankowska ◽  
Grzegorz Satała ◽  
Andrzej J. Bojarski ◽  
Maciej Pawłowski ◽  
Grażyna Chłoń-Rzepa
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Inhibitory Activity ◽  
Glycogen Synthase ◽  
Neuropsychiatric Symptoms ◽  
New Drugs ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Multifunctional Ligands

: Alzheimer’s disease (AD) belongs to the most common forms of dementia that causes a progressive loss of brain cells and leads to memory impairment and decline of other thinking skills. There is yet no effective treatment for AD; hence, the search for new drugs that could improve memory and other cognitive functions is one of the hot research topics worldwide. Scientific efforts are also directed toward combating behavioral and psychological symptoms of dementia, which are an integral part of the disease. Several studies have indicated that glycogen synthase kinase 3 beta (GSK3β) plays a crucial role in the pathogenesis of AD. Moreover, GSK3β inhibition provided beneficial effects on memory improvement in multiple animal models of AD. The present review aimed to update the most recent reports on the discovery of novel multifunctional ligands with GSK3β inhibitory activity as potential drugs for the symptomatic and disease-modifying therapy of AD. Compounds with GSK3β inhibitory activity seem to be an effective pharmacological approach for treating the causes and symptoms of AD as they reduced neuroinflammation and pathological hallmarks in animal models of AD and provided relief from cognitive and neuropsychiatric symptoms. These compounds have the potential to be used as drugs for the treatment of AD, but their precise pharmacological, pharmacokinetic, toxicological, and clinical profiles need to be defined.

scholarly journals Glycogen Synthase Kinase 3 Is an Insulin-Regulated C/EBPα Kinase

1999 ◽  
Vol 19 (12) ◽  
pp. 8433-8441 ◽  
Author(s):  
Sarah E. Ross ◽  
Robin L. Erickson ◽  
Nahid Hemati ◽  
Ormond A. MacDougald
Keyword(s):  
Conformational Changes ◽  
Kinase Inhibitor ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Phosphatidylinositol 3 Kinase ◽  
Pharmacological Agents ◽  
Enhancer Binding Protein

ABSTRACT CCAAT/enhancer binding protein α (C/EBPα) is a transcription factor involved in creating and maintaining the adipocyte phenotype. We have shown previously that insulin stimulates dephosphorylation of C/EBPα in 3T3-L1 adipocytes. Studies to identify the insulin-sensitive sites of phosphorylation reveal that a C/EBPα peptide (amino acids H215 to K250) is phosphorylated on T222, T226, and S230 in vivo. The context of these phosphoamino acids implicates glycogen synthase kinase 3 (GSK3), whose activity is known to be repressed in response to insulin, as a potential kinase for phosphorylation of T222 and T226. Accordingly, GSK3 phosphorylates the predicted region of C/EBPα on threonine in vitro, and GSK3 uses C/EBPα as a substrate in vivo. In addition, the effect of pharmacological agents on GSK3 activity correlates with regulation of C/EBPα phosphorylation. Treatment of 3T3-L1 adipocytes with the phosphatidylinositol 3-kinase inhibitor wortmannin results in phosphorylation of C/EBPα, whereas treatment with the GSK3 inhibitor lithium results in dephosphorylation of C/EBPα. Collectively, these data indicate that insulin stimulates dephosphorylation of C/EBPα on T222 and T226 through inactivation of GSK3. Since dephosphorylation of C/EBPα in response to lithium is blocked by okadaic acid, strong candidates for the T222 and T226 phosphatase are protein phosphatases 1 and 2a. Treatment of adipocytes with insulin alters the protease accessibility of widespread sites within the N terminus of C/EBPα, consistent with phosphorylation causing profound conformational changes. Finally, phosphorylation of C/EBPα and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes.

scholarly journals Assembly Protein Precursor (pUL80.5 Homolog) of Simian Cytomegalovirus Is Phosphorylated at a Glycogen Synthase Kinase 3 Site and Its Downstream “Priming” Site: Phosphorylation Affects Interactions of Protein with Itself and with Major Capsid Protein

2004 ◽  
Vol 78 (24) ◽  
pp. 13501-13511 ◽  
Author(s):  
Rebecca J. Casaday ◽  
Justin R. Bailey ◽  
Suzanne R. Kalb ◽  
Edward J. Brignole ◽  
Amy N. Loveland ◽  
...  
Keyword(s):  
Capsid Protein ◽  
Conformational Changes ◽  
Major Capsid Protein ◽  
Glycogen Synthase ◽  
Consensus Sequence ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Protein Precursor

ABSTRACT Capsid assembly among the herpes-group viruses is coordinated by two related scaffolding proteins. In cytomegalovirus (CMV), the main scaffolding constituent is called the assembly protein precursor (pAP). Like its homologs in other herpesviruses, pAP is modified by proteolytic cleavage and phosphorylation. Cleavage is essential for capsid maturation and production of infectious virus, but the role of phosphorylation is undetermined. As a first step in evaluating the significance of this modification, we have identified the specific sites of phosphorylation in the simian CMV pAP. Two were established previously to be adjacent serines (Ser156 and Ser157) in a casein kinase II consensus sequence. The remaining two, identified here as Thr231 and Ser235, are within consensus sequences for glycogen synthase kinase 3 (GSK-3) and mitogen-activated protein kinase, respectively. Consistent with Thr231 being a GSK-3 substrate, its phosphorylation required a downstream “priming” phosphate (i.e., Ser235) and was reduced by a GSK-3-specific inhibitor. Phosphorylation of Ser235 converts pAP to an electrophoretically slower-mobility isoform, pAP*; subsequent phosphorylation of pAP* at Thr231 converts pAP* to a still-slower isoform, pAP**. The mobility shift to pAP* was mimicked by substituting an acidic amino acid for either Thr231 or Ser235, but the shift to pAP** required that both positions be phosphorylated. Glu did not substitute for pSer235 in promoting phosphorylation of Thr231. We suggest that phosphorylation of Thr231 and Ser235 causes charge-driven conformational changes in pAP, and we demonstrate that preventing these modifications alters interactions of pAP with itself and with major capsid protein, suggesting a functional significance.

scholarly journals Reconstructing three-dimensional shape envelopes from time-resolved small-angle X-ray scattering data

2008 ◽  
Vol 41 (6) ◽  
pp. 1046-1052 ◽  
Author(s):  
Jessica Lamb ◽  
Lisa Kwok ◽  
Xiangyun Qiu ◽  
Kurt Andresen ◽  
Hye Yoon Park ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Small Angle ◽  
Three Dimensional ◽  
Model Systems ◽  
Scattering Data ◽  
Time Resolved ◽  
X Ray ◽  
X Ray Scattering ◽  
Group I ◽  
Ray Scattering

Modern computing power has made it possible to reconstruct low-resolution, three-dimensional shapes from solution small-angle X-ray scattering (SAXS) data on biomolecules withouta prioriknowledge of the structure. In conjunction with rapid mixing techniques, SAXS has been applied to time resolve conformational changes accompanying important biological processes, such as biomolecular folding. In response to the widespread interest in SAXS reconstructions, their value in conjunction with such time-resolved data has been examined. The group I intron fromTetrahymena thermophilaand its P4–P6 subdomain are ideal model systems for investigation owing to extensive previous studies, including crystal structures. The goal of this paper is to assay the quality of reconstructions from time-resolved data given the sacrifice in signal-to-noise required to obtain sharp time resolution.

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