scholarly journals A double role of the Gal80 N terminus in activation of transcription by Gal4p

2020 ◽  
Vol 3 (12) ◽  
pp. e202000665
Author(s):  
Annekathrin Reinhardt-Tews ◽  
Rościsław Krutyhołowa ◽  
Christian Günzel ◽  
Constance Roehl ◽  
Sebastian Glatt ◽  
...  
Keyword(s):  
Kluyveromyces Lactis ◽  
Transcription Activation ◽  
Nuclear Accumulation ◽  
Divergent Evolution ◽  
Catalytic Center ◽  
Transcription Activation Domain ◽  
Activation Of Transcription ◽  
Regulatory Module ◽  
N Terminus

The yeast galactose switch operated by the Gal4p–Gal80p–Gal3p regulatory module is a textbook model of transcription regulation in eukaryotes. The Gal80 protein inhibits Gal4p-mediated transcription activation by binding to the transcription activation domain. In Saccharomyces cerevisiae, inhibition is relieved by formation of an alternative Gal80–Gal3 complex. In yeasts lacking a Gal3p ortholog, such as Kluyveromyces lactis, the Gal1 protein (KlGal1p) combines regulatory and enzymatic activity. The data presented here reveal a yet unknown role of the KlGal80 N terminus in the mechanism of Gal4p activation. The N terminus contains an NLS, which is responsible for nuclear accumulation of KlGal80p and KlGal1p and for KlGal80p-mediated galactokinase inhibition. Herein, we present a model where the N terminus of KlGal80p reaches the catalytic center of KlGal1p causing enzyme inhibition in the nucleus and stabilization of the KlGal1–KlGal80p complex. We corroborate this model by genetic analyses and structural modelling and provide a rationale for the divergent evolution of the mechanism activating Gal4p.

scholarly journals A double role of the Gal80 N-terminus in activation of transcription by Gal4p

2020 ◽  
Author(s):  
Annekathrin Reinhardt-Tews ◽  
Rościsław Krutyhołowa ◽  
Christian Günzel ◽  
Sebastian Glatt ◽  
Karin D Breunig
Keyword(s):  
Transcription Activation ◽  
Nuclear Accumulation ◽  
Divergent Evolution ◽  
Nuclear Fraction ◽  
Catalytic Center ◽  
Activation Of Transcription ◽  
Regulatory Module ◽  
N Terminus

ABSTRACTThe yeast galactose switch operated by the Gal4p-Gal80p-Gal3p regulatory module is a textbook model of transcription regulation in eukaryotes. The Gal80 protein inhibits Gal4p-mediated transcription activation by binding to the transcription activation domain. Inhibition is relieved by formation of an alternative Gal80-Gal3 complex. In yeasts lacking a Gal3p ortholog the Gal1 protein combines regulatory and enzymatic activity. The data presented here reveal a so-far unknown role of the Gal80 N-terminus in the mechanism of Gal4p activation. The N-terminus contains an NLS, which is responsible for nuclear accumulation of KlGal80p and galactokinase inhibition in vitro. Herein we propose a model where the N-terminus of KlGal80p reaches into the catalytic center of KlGal1p of the nuclear fraction of KlGal1p triggering dissociation of the KlGal80-KlGal4 complex. We corroborate this model by genetic analyses and structural modelling and provide a rationale for the divergent evolution of the mechanism activating Gal4p.Summary blurbActivation of gene expression by Gal4p in K. lactis requires an element in the N-terminus of KlGal80 that mediates nuclear import, KlGal1 interaction and galactokinase inhibition

The role of SERT N-terminus in amphetamine-induced efflux

2016 ◽  
Vol 4 (Suppl. 3) ◽  
pp. A4.17
Author(s):  
Fatma Aslı Erdem
Keyword(s):  
N Terminus

scholarly journals RNA Helicase A Regulates the Replication of RNA Viruses

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 361
Author(s):  
Rui-Zhu Shi ◽  
Yuan-Qing Pan ◽  
Li Xing
Keyword(s):  
Virus Replication ◽  
Rna Binding ◽  
Rna Viruses ◽  
Rna Helicase ◽  
Rna Helicase A ◽  
Double Stranded Rna ◽  
Binding Domains ◽  
N Terminus

The RNA helicase A (RHA) is a member of DExH-box helicases and characterized by two double-stranded RNA binding domains at the N-terminus. RHA unwinds double-stranded RNA in vitro and is involved in RNA metabolisms in the cell. RHA is also hijacked by a variety of RNA viruses to facilitate virus replication. Herein, this review will provide an overview of the role of RHA in the replication of RNA viruses.

scholarly journals Oncogenic UBE3C promotes breast cancer progression by activating Wnt/β-catenin signaling

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chen Hang ◽  
Shanojie Zhao ◽  
Tiejun Wang ◽  
Yan Zhang
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Nuclear Accumulation ◽  
Migration And Invasion ◽  
Ubiquitin Protein Ligase ◽  
Novel Target ◽  
First Time ◽  
Breast Tissues

Abstract Background Breast cancer (BrCa) is the most common female malignancy worldwide and has the highest morbidity among all cancers in females. Unfortunately, the mechanisms of BrCa growth and metastasis, which lead to a poor prognosis in BrCa patients, have not been well characterized. Methods Immunohistochemistry (IHC) was performed on a BrCa tissue microarray (TMA) containing 80 samples to evaluate ubiquitin protein ligase E3C (UBE3C) expression. In addition, a series of cellular experiments were conducted to reveal the role of UBE3C in BrCa. Results In this research, we identified UBE3C as an oncogenic factor in BrCa growth and metastasis for the first time. UBE3C expression was upregulated in BrCa tissues compared with adjacent breast tissues. BrCa patients with high nuclear UBE3C expression in tumors showed remarkably worse overall survival (OS) than those with low nuclear expression. Knockdown of UBE3C expression in MCF-7 and MDA-MB-453 BrCa cells inhibited cell proliferation, migration and invasion in vitro, while overexpression of UBE3C in these cells exerted the opposite effects. Moreover, UBE3C promoted β-catenin nuclear accumulation, leading to the activation of the Wnt/β-catenin signaling pathway in BrCa cells. Conclusion Collectively, these results imply that UBE3C plays crucial roles in BrCa development and progression and that UBE3C may be a novel target for the prevention and treatment of BrCa.

scholarly journals The Role of Arg13 in Protein Phosphatase M tPphA from Thermosynechococcus elongatus

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Jiyong Su ◽  
Karl Forchhammer
Keyword(s):  
Amino Acid ◽  
Protein Phosphatase ◽  
Arginine Residue ◽  
Side Chain ◽  
Wild Type ◽  
Catalytic Center ◽  
Nitrophenyl Phosphate ◽  
Reduced Activity ◽  
Amino Acid Variants

A highly conserved arginine residue is close to the catalytic center of PPM/PP2C-type protein phosphatases. Different crystal structures of PPM/PP2C homologues revealed that the guanidinium side chain of this arginine residue can adopt variable conformations and may bind ligands, suggesting an important role of this residue during catalysis. In this paper, we randomly mutated Arginine 13 of tPphA, a PPM/PP2C-type phosphatase from Thermosynechococcus elongatus, and obtained 18 different amino acid variants. The generated variants were tested towards p-nitrophenyl phosphate and various phosphopeptides. Towards p-nitrophenyl phosphate as substrate, twelve variants showed 3–7 times higher Km values than wild-type tPphA and four variants (R13D, R13F, R13L, and R13W) completely lost activity. Strikingly, these variants were still able to dephosphorylate phosphopeptides, although with strongly reduced activity. The specific inability of some Arg-13 variants to hydrolyze p-nitrophenyl phosphate highlights the importance of additional substrate interactions apart from the substrate phosphate for catalysis. The properties of the R13 variants indicate that this residue assists in substrate binding.

scholarly journals Chimeric elk/mouse prion proteins in transgenic mice

2013 ◽  
Vol 94 (2) ◽  
pp. 443-452 ◽  
Author(s):  
Gültekin Tamgüney ◽  
Kurt Giles ◽  
Abby Oehler ◽  
Natrina L. Johnson ◽  
Stephen J. DeArmond ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Prion Proteins ◽  
Second Line ◽  
Mouse Line ◽  
Wasting Disease ◽  
C Terminus ◽  
Incubation Periods ◽  
N Terminus ◽  
Mouse Lines

Chronic wasting disease (CWD) of deer and elk is a highly communicable neurodegenerative disorder caused by prions. Investigations of CWD are hampered by slow bioassays in transgenic (Tg) mice. Towards the development of Tg mice that will be more susceptible to CWD prions, we created a series of chimeric elk/mouse transgenes that encode the N terminus of elk PrP (ElkPrP) up to residue Y168 and the C terminus of mouse PrP (MoPrP) beyond residue 169 (mouse numbering), designated Elk3M(SNIVVK). Between codons 169 and 219, six residues distinguish ElkPrP from MoPrP: N169S, T173N, V183I, I202V, I214V and R219K. Using chimeric elk/mouse PrP constructs, we generated 12 Tg mouse lines and determined incubation times after intracerebral inoculation with the mouse-passaged RML scrapie or Elk1P CWD prions. Unexpectedly, one Tg mouse line expressing Elk3M(SNIVVK) exhibited incubation times of <70 days when inoculated with RML prions; a second line had incubation times of <90 days. In contrast, mice expressing full-length ElkPrP had incubation periods of >250 days for RML prions. Tg(Elk3M,SNIVVK) mice were less susceptible to CWD prions than Tg(ElkPrP) mice. Changing three C-terminal mouse residues (202, 214 and 219) to those of elk doubled the incubation time for mouse RML prions and rendered the mice resistant to Elk1P CWD prions. Mutating an additional two residues from mouse to elk at codons 169 and 173 increased the incubation times for mouse prions to >300 days, but made the mice susceptible to CWD prions. Our findings highlight the role of C-terminal residues in PrP that control the susceptibility and replication of prions.

Oxidative Stress and Cancer: The Role of Nrf2

2018 ◽  
Vol 18 (6) ◽  
pp. 538-557 ◽  
Author(s):  
Soraya Sajadimajd ◽  
Mozafar Khazaei
Keyword(s):  
Oxidative Stress ◽  
Cell Fate ◽  
Nuclear Import ◽  
Tyrosine Kinases ◽  
Oxidative Enzymes ◽  
Nuclear Accumulation ◽  
Constitutive Activation ◽  
Number Of Genes ◽  
Electrophilic Stress

Oxidative stress due to imbalance between ROS production and detoxification plays a pivotal role in determining cell fate. In response to the excessive ROS, apoptotic signaling pathway is activated to promote normal cell death. However, through deregulation of biomolecules, high amount of ROS promotes carcinogenesis in cells with defective signaling factors. In this line, NRF2 appears to be as a master regulator, which protects cells from oxidative and electrophilic stress. Nrf2 is an intracellular transcription factor that regulates the expression of a number of genes to encode anti-oxidative enzymes, detoxifying factors, anti-apoptotic proteins and drug transporters. Under normal condition, Nrf2 is commonly degraded in cytoplasm by interaction with Keap1 inhibitor as an adaptor for ubiquitination factors. However, high amount of ROS activates tyrosine kinases to dissociate Nrf2: Keap1 complex, nuclear import of Nrf2 and coordinated activation of cytoprotective gene expression. Nevertheless, deregulation of Nrf2 and/or Keap1 due to mutation and activated upstream oncogenes is associated with nuclear accumulation and constitutive activation of Nrf2 to protect cells from apoptosis and induce proliferation, metastasis and chemoresistance. Owning to the interplay of ROS and Nrf2 signaling pathways with carcinogenesis, Nrf2 modulation seems to be important in the personalization of cancer therapy.

scholarly journals Role of the N-terminus in the structure and stability of chicken annexin V

FEBS Letters ◽  
1997 ◽  
Vol 416 (2) ◽  
pp. 217-220 ◽  
Author(s):  
David Arboledas ◽  
Nieves Olmo ◽  
Mª Antonia Lizarbe ◽  
Javier Turnay
Keyword(s):  
Annexin V ◽  
Structure And Stability ◽  
N Terminus

Isolation and characterization of SRF accessory proteins

1993 ◽  
Vol 340 (1293) ◽  
pp. 325-332 ◽  
Keyword(s):  
Ternary Complex ◽  
Map Kinases ◽  
Serum Response Factor ◽  
Regulatory Element ◽  
Isolation And Characterization ◽  
Activation Of Transcription ◽  
Serum Response ◽  
Dna Binding Properties

Many genes which are regulated by growth factors contain a common regulatory element, the serum response element (SRE). Activation of transcription by the SRE involves a ternary complex formed between a ubiquitous factor, serum response factor (SRF), and a second protein, p62/TCF. We used a yeast genetic screen to isolate cDNAs encoding a protein, SAP-1, with the DNA binding properties of p62/TCF. The SAP-1 sequence contains three regions of homology to the previously uncharacterized Elk-1 protein, which also acts as an SRF accessory protein. Only two of these regions are required for cooperative interactions with SRF in the ternary complex. The third contains several conserved sites for the MAP kinases, whose activity is regulated in response to growth factor stimulation. We discuss the potential role of these proteins in regulation of the c-fos SRE.

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