Article
Multidisciplinary Sciences
Andrea Piserchio, Kimberly J. Long, Luke S. Browning, Amanda L. Bohanon, Eta A. Isiorho, Kevin N. Dalby, Ranajeet Ghose
Summary: Protein translation, a high-energy process, requires robust regulation under energy-deprived conditions. The eEF-2K plays a crucial role in this regulation by suppressing translational elongation through phosphorylation of eEF-2. It has been suggested that eEF-2K's response to energy levels is mediated by AMPK and the mTOR pathway.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Andrea Piserchio, Kimberly Long, Kwangwoon Lee, Eric A. Kumar, Rinat Abzalimov, Kevin N. Dalby, Ranajeet Ghose
Summary: In this study, the conformational changes during complex formation between CaM-activated eEF-2K and TR, as well as the effects of TR autophosphorylation at Thr348, were investigated using a combination of HXMS, solution-state NMR, and biochemical approaches. The results suggest that the C-lobe surface of CaM interacts with TR and the helix F of CaM responds to Thr348 phosphorylation and pH changes, playing a crucial role in inducing conformational changes in TR for efficient phosphorylation.
Article
Pharmacology & Pharmacy
Tomoko Kodama, Kosuke Otani, Muneyoshi Okada, Hideyuki Yamawaki
Summary: This study demonstrates for the first time that the selective eEF2 kinase inhibitor A484954 can induce vasodilatation by inhibiting sympathetic nerve activity-induced vasoconstriction.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2022)
Article
Cell Biology
Mumin Alper Erdogan, Ahmed Ashour, Erkan Yuca, Kivanc Gorgulu, Bulent Ozpolat
Summary: EF2K is highly upregulated in ovarian cancer cells and associated with disease progression and survival, promoting cell proliferation and invasion. Targeting EF2K can inhibit ovarian tumor growth and metastasis, inducing apoptosis.
CELLULAR SIGNALLING
(2021)
Article
Agriculture, Multidisciplinary
Lianyun Lin, Heng Jiang, Hadiatullah Hadiatullah, Ruifang Ma, Henryk Korza, Yucheng Gu, Zhiguang Yuchi
Summary: The study reveals that insect calmodulin (CaM) regulates the RyR receptor in agricultural pests, and the enhanced binding of CaM in mutant insect RyR leads to increased sensitivity to insecticides, suggesting the potential targeting of the CaM-CaMBD interface by molecular glues.
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Tomohiro Miyoshi, Takaomi Nomura, Koich Takeya, Toshio Uchiumi
Summary: A cyclic hexapeptide, RA-VII, isolated from the Rubiaceae family of plants, has high cytotoxic activity. The mechanism of its action on protein synthesis is not clear. This study shows that RA-VII inhibits polyphenylalanine synthesis and prevents the GTPase activity of eEF2/ribosome complex, suggesting that it stabilizes the GTP.eEF2 complex structure and suppresses normal turnover of eEF2 after translocation.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Cell Biology
Faten Abdelli, Karim Jellali, Estefania Anguita, Maria Gonzalez-Munoz, Eduardo Villalobo, Ivan Madronal, Juan Alcalde, Mamdouh Ben Ali, Jihene Elloumi-Mseddi, Ikram Jemel, Francesc Tebar, Carlos Enrich, Sami Aifa, Antonio Villalobo
Summary: The study shows that EGFR with CaM-BD and CaM-LD domains affects the receptor's TK activity. Different EGFR mutants exhibit varying abilities to bind EGF, localize to the plasma membrane, and undergo ligand-dependent internalization.
JOURNAL OF CELLULAR PHYSIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Ferah Comert Onder, Serdar Durdagi, Nermin Kahraman, Tugce Nur Uslu, Hakan Kandemir, Esen Bellur Atici, Bulent Ozpolat, Mehmet Ay
Summary: In this study, novel compounds were designed and synthesized to inhibit eEF2K activity in breast cancer cells, showing promising results in vitro. These compounds may serve as potential therapeutic agents for cancer treatment and warrant further evaluation in preclinical tumor models for clinical translation.
BIOORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Byung-Sik Shin, Ivaylo P. Ivanov, Joo-Ran Kim, Chune Cao, Terri G. Kinzy, Thomas E. Dever
Summary: Diphthamide (DPH) is a conserved amino acid modification on eukaryotic translation elongation factor eEF2. Loss of DPH impairs translational fidelity, leading to increased rates of ribosomal frameshifting and premature termination at out-of-frame stop codons. The ADP-ribosylation of DPH by bacterial toxins inhibits the binding of eEF2 to elongating ribosomes, further compromising translation accuracy. The costly, yet non-essential, DPH modification has been conserved through evolution to maintain translational fidelity.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Multidisciplinary Sciences
Muminjon Djumagulov, Natalia Demeshkina, Lasse Jenner, Alexey Rozov, Marat Yusupov, Gulnara Yusupova
Summary: Translation of the genetic code into proteins in eukaryotes is facilitated by eEF2 and tRNA modifications, whose specific functions in translocation accuracy are not fully understood. A high-resolution X-ray structure of the eukaryotic 80S ribosome in a translocation-intermediate state reveals the network of stabilization of codon-anticodon interactions involving diphthamide and wybutosine, emphasizing the role of eEF2 as a 'pawl' in defining translocation directionality. This model demonstrates the large-scale molecular reorganizations of eukaryotic specific elements to maintain mRNA reading frame during translocation.
Article
Biochemistry & Molecular Biology
Zheren Ou, Alexey Petrov
Summary: The Intergenic Region Internal Ribosome Entry Sites (IGR IRESs) of Discistroviridae promote protein synthesis without initiation factors, with IRES translocation by elongation factor 2 (eEF2) being the first factor-catalysed reaction. A single-molecule labeling system was developed to observe the intersubunit conformation of eukaryotic ribosomes and study the translation initiation and translocation of cricket paralysis virus IRES (CrPV IRES). It was found that eEF2 promotes the mid and late stages of CrPV IRES translocation by unlocking ribosomal movements, and sordarin, an antifungal drug, enhances the efficiency of translocation by stabilizing eEF2 on the ribosome.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Cell Biology
Daniel Romaus-Sanjurjo, Junmi M. Saikia, Hugo J. Kim, Kristen M. Tsai, Geneva Q. Le, Binhai Zheng
Summary: The study demonstrates that overexpression of eEF1A2 enhances collateral sprouting of CST neurons, likely through increased protein synthesis, mTOR signaling, and actin cytoskeleton rearrangement.
CELL DEATH DISCOVERY
(2022)
Article
Biochemistry & Molecular Biology
Alexander Zhdanov, Anna Golubeva, Martina M. Yordanova, Dmitry E. Andreev, Ana Paula Ventura-Silva, Harriet Schellekens, Pavel Baranov, John F. Cryan, Dmitri B. Papkovsky
Summary: Activated ghrelin receptor GHS-R1 alpha regulates energy homeostasis and biosynthetic processes. New research shows that ghrelin can rapidly enhance protein synthesis in cells by dephosphorylating eEF2. This translation activation process may contribute to the rapid replenishment of neuropeptides released upon GHS-R1a activation.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Tomoko Kodama, Satoshi Kameshima, Kosuke Otani, Muneyoshi Okada, Hideyuki Yamawaki
Summary: This study revealed for the first time that A484954 induces diuretic effect in SHR at least partly through renal vasorelaxation via β3-adrenergic receptor.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Plant Sciences
Lei Xu, Lixia Zhang, Yajiao Liu, Bilig Sod, Mingna Li, Tianhui Yang, Ting Gao, Qingchuan Yang, Ruicai Long
Summary: This study identified EF genes in Medicago truncatula and investigated the salt stress response function of MtEF1A1. The results showed that overexpression of MtEF1A1 enhanced plant resistance to salt stress and reduced oxidative stress levels. Additionally, the expression levels of stress-responsive and calcium-binding genes were upregulated in MtEF1A1-overexpressing M. truncatula.
Article
Neurosciences
Christopher Heise, Elham Taha, Luca Murru, Luisa Ponzoni, Angela Cattaneo, Fabrizia C. Guarnieri, Caterina Montani, Adele Mossa, Elena Vezzoli, Giulio Ippolito, Jonathan Zapata, Iliana Barrera, Alexey G. Ryazanov, James Cook, Michael Poe, Michael Rajesh Stephen, Maksym Kopanitsa, Roberta Benfante, Francesco Rusconi, Daniela Braida, Maura Francolini, Christopher G. Proud, Flavia Valtorta, Maria Passafaro, Mariaelvina Sala, Angela Bachi, Chiara Verpelli, Kobi Rosenblum, Carlo Sala
Review
Oncology
Xuemin Wang, Jianling Xie, Christopher G. Proud
Article
Biochemistry & Molecular Biology
Athanasios Papakyriakou, Emma Reeves, Mary Beton, Halina Mikolajek, Leon Douglas, Grace Cooper, Tim Elliott, Jorn M. Werner, Edward James
JOURNAL OF BIOLOGICAL CHEMISTRY
(2018)
Article
Biochemistry & Molecular Biology
Anthony O. Fedele, Christopher G. Proud
BIOSCIENCE REPORTS
(2020)
Article
Biochemistry & Molecular Biology
Thomas D. Burton, Anthony O. Fedele, Jianling Xie, Lauren Y. Sandeman, Christopher G. Proud
JOURNAL OF BIOLOGICAL CHEMISTRY
(2020)
Article
Biochemistry & Molecular Biology
James E. Merrett, Jianling Xie, Peter J. Psaltis, Christopher G. Proud
BIOCHEMICAL JOURNAL
(2020)
Article
Biochemistry & Molecular Biology
Yu Wu, Jianling Xie, Xin Jin, Roman Lenchine, Xuemin Wang, Danielle M. Fang, Zeyad D. Nassar, Lisa M. Butler, Jing Li, Christopher G. Proud
BIOCHEMICAL JOURNAL
(2020)
Article
Biochemistry & Molecular Biology
Anthony O. Fedele, Valerie Carraro, Jianling Xie, Julien Averous, Christopher G. Proud
JOURNAL OF BIOLOGICAL CHEMISTRY
(2020)
Article
Biochemistry & Molecular Biology
Luis F. H. Gladulich, Jianling Xie, Kirk B. Jensen, Makoto Kamei, Roberto Paes-de-Carvalho, Marcelo Cossenza, Christopher G. Proud
Summary: This study investigated the localization control of eEF2K and its impact on protein synthesis in neuronal cells. Modifying eEF2K function through pharmacological and/or genetic approaches revealed that eEF2K activity and localization can be regulated by its binding partner Homer1b/c and the mTORC1 signaling pathway.
JOURNAL OF NEUROCHEMISTRY
(2021)
Article
Genetics & Heredity
Inna Slynko, Stephanie Nguyen, Eline M. C. Hamilton, Lisanne E. Wisse, Iwan J. P. de Esch, Chris de Graaf, John B. Bruning, Christopher G. Proud, Truus E. M. Abbink, Marjo S. van der Knaap
Summary: This study analyzed 97 missense mutations in vanishing white matter disease (VWM) and found that over 50% of mutations have (ultra-)severe phenotypic effects. Approximately 60% of mutations affect the ε-subunit containing the catalytic domain, while about 36% affect subunit interfaces, mostly with severe effects.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2021)
Article
Biotechnology & Applied Microbiology
Stuart P. De Poi, Jianling Xie, C. Mark Smales, Christopher G. Proud
Summary: The study demonstrates that expressing certain constitutively active mutants of Rheb in CHO cells can lead to faster protein synthesis and increased secretion of valuable proteins, providing a simple approach to promoting cell growth and production of high commercial value secreted proteins in defined media.
BIOTECHNOLOGY AND BIOENGINEERING
(2021)
Article
Biochemistry & Molecular Biology
Roman Lenchine, Sushma R. Rao, Xuemin Wang, Danielle Meiwen Fang, Christopher G. Proud
Summary: Cells in solid tumors can survive under nutrient deprivation by utilizing autophagy and eEF2K mechanisms, regulated by AMP-activated protein kinase and mechanistic target of rapamycin complex 1 signaling pathways. Disrupting both autophagy and eEF2K compromises the survival of lung and breast cancer cells, highlighting the importance of these processes in cancer cell survival.
BIOCHEMICAL JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Jianling Xie, Stuart P. De Poi, Sean J. Humphrey, Leanne K. Hein, John B. Bruning, Wenru Pan, Luke A. Selth, Timothy J. Sargeant, Christopher G. Proud
Summary: The study demonstrates that various recurrent Rheb mutations drive hyperactive mTORC1 signaling through different levels of insensitivity to the main inhibitor of Rheb, tuberous sclerosis complex. Among them, two activated mutants, Rheb-T23M and E40K, significantly promote cell growth, proliferation, and anchorage-independent growth, leading to enhanced tumor growth in vivo. Proteomic analysis reveals that these mutants activate distinct oncogenic pathways, with Rheb-T23M enhancing anaerobic glycolysis and Rheb-E40K regulating eEF2 and autophagy, possibly through interactions with AMPK.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Xuemin Wang, Christopher G. Proud
Summary: Control of protein synthesis is crucial in shaping the proteome and physiological responses. Phosphorylation of eIF2 and the integrated stress response (ISR) play key roles in regulating protein synthesis. Recent studies have uncovered new features of eIF2 control and the ISR, suggesting potential therapeutic value in interfering with the ISR in certain settings, such as VWM.
BIOCHEMICAL JOURNAL
(2022)
Review
Pharmacology & Pharmacy
Xin Jin, Tingting Qiu, Li Li, Rilei Yu, Xiguang Chen, Changgui Li, Christopher G. Proud, Tao Jiang
Summary: The occurrence of obesity has increased worldwide and contributes to the development of various diseases. Excess energy intake leads to adipocyte hypertrophy, hyperplasia, and visceral fat formation, resulting in cardiovascular and liver diseases. Adipose tissue can secrete adipokines and cytokines, causing insulin resistance and hyperglycemia, exacerbating obesity-related diseases. Although progress has been made in obesity treatment, the progression and pathogenesis of obesity-induced diseases are still unclear. Understanding their links is essential for better management and treatment.
ACTA PHARMACEUTICA SINICA B
(2023)