The Experts below are selected from a list of 25605 Experts worldwide ranked by ideXlab platform
David Harrich - One of the best experts on this subject based on the ideXlab platform.
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Binding of the Eukaryotic Translation elongation factor 1A with the 5’UTR of HIV-1 genomic RNA is important for reverse transcription
Virology journal, 2015Co-Authors: Ting Wei, Hongping Jin, Amanda Rose, Rui Wang, Min-hsuan Lin, Kirsten Spann, David HarrichAbstract:Background The cellular protein Eukaryotic Translation elongation factor 1A (eEF1A) binds to aminoacylated transfer RNAs and delivers them to the ribosome during Translation. eEF1A also binds to RNA secondary structures present in genomes of several RNA viruses and plays important roles in their replication. As a RNA binding protein, whether eEF1A can bind with HIV-1 genomic RNA has not been investigated and was the aim of the study.
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The Unexpected Roles of Eukaryotic Translation Elongation Factors in RNA Virus Replication and Pathogenesis
Microbiology and molecular biology reviews : MMBR, 2013Co-Authors: Ting Wei, Catherine M. Abbott, David HarrichAbstract:The prokaryotic Translation elongation factors were identified as essential cofactors for RNA-dependent RNA polymerase activity of the bacteriophage Qβ more than 40 years ago. A growing body of evidence now shows that Eukaryotic Translation elongation factors (eEFs), predominantly eEF1A, acting in partially characterized complexes sometimes involving additional eEFs, facilitate virus replication. The functions of eEF1A as a protein chaperone and an RNA- and actin-binding protein enable its "moonlighting" roles as a virus replication cofactor. A diverse group of viruses, from human immunodeficiency type 1 and West Nile virus to tomato bushy stunt virus, have adapted to use eEFs as cofactors for viral transcription, Translation, assembly, and pathogenesis. Here we review the mechanisms used by viral pathogens to usurp these abundant cellular proteins for their replication.
Jerry Pelletier - One of the best experts on this subject based on the ideXlab platform.
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General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation.
International journal of molecular sciences, 2020Co-Authors: Leo Shen, Jerry PelletierAbstract:DExD (DDX)- and DExH (DHX)-box RNA helicases, named after their Asp-Glu-x-Asp/His motifs, are integral to almost all RNA metabolic processes in Eukaryotic cells. They play myriad roles in processes ranging from transcription and mRNA-protein complex remodeling, to RNA decay and Translation. This last facet, Translation, is an intricate process that involves DDX/DHX helicases and presents a regulatory node that is highly targetable. Studies aimed at better understanding this family of conserved proteins have revealed insights into their structures, catalytic mechanisms, and biological roles. They have also led to the development of chemical modulators that seek to exploit their essential roles in diseases. Herein, we review the most recent insights on several general and target-specific DDX/DHX helicases in Eukaryotic Translation initiation.
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Therapeutic Opportunities in Eukaryotic Translation.
Cold Spring Harbor perspectives in biology, 2018Co-Authors: Jennifer Chu, Jerry PelletierAbstract:The ability to block biological processes with selective small molecules provides advantages distinct from most other experimental approaches. These include rapid time to onset, swift reversibility, ability to probe activities in manners that cannot be accessed by genetic means, and the potential to be further developed as therapeutic agents. Small molecule inhibitors can also be used to alter expression and activity without affecting the stoichiometry of interacting partners. These tenets have been especially evident in the field of Translation. Small molecule inhibitors were instrumental in enabling investigators to capture short-lived complexes and characterize specific steps of protein synthesis. In addition, several drugs that are the mainstay of modern antimicrobial drug therapy are potent inhibitors of prokaryotic Translation. Currently, there is much interest in targeting Eukaryotic Translation as decades of research have revealed that deregulated protein synthesis in cancer cells represents a targetable vulnerability. In addition to being potential therapeutics, small molecules that manipulate Translation have also been shown to influence cognitive processes such as memory. In this review, we focus on small molecule modulators that target the Eukaryotic Translation initiation apparatus and provide an update on their potential application to the treatment of disease.
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Inhibitors of Translation targeting Eukaryotic Translation initiation factor 4A.
Methods in enzymology, 2012Co-Authors: Regina Cencic, Gabriela Galicia-vázquez, Jerry PelletierAbstract:The RNA helicases eIF4AI and eIF4AII play key roles in recruiting ribosomes to mRNA templates during Eukaryotic Translation initiation. Small molecule inhibitors of eIF4AI and eIF4AII have been useful for chemically dissecting their role in Translation in vitro and in vivo. Here, we describe a screen performed on a small focused library of kinase inhibitors to identify a novel helicase inhibitor. We describe assays that have been critical for characterizing novel RNA helicase inhibitors.
Katherine L. B. Borden - One of the best experts on this subject based on the ideXlab platform.
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Biochemical and Structural Insights into the Eukaryotic Translation Initiation Factor eIF4E
Current protein & peptide science, 2019Co-Authors: L Volpon, Michael J. Osborne, Katherine L. B. BordenAbstract:A major question in cell and cancer biology is concerned with understanding the flow of information from gene to protein. Indeed, many studies indicate that the proteome can be decoupled from the transcriptome. A major source of this decoupling is post-transcriptional regulation. The Eukaryotic Translation initiation factor eIF4E serves as an excellent example of a protein that can modulate the proteome at the post-transcriptional level. eIF4E is elevated in many cancers thus highlighting the relevance of this mode of control to biology. In this review, we provide a brief overview of various functions of eIF4E in RNA metabolism e.g. in nuclear-cytoplasmic RNA export, Translation, RNA stability and/or sequestration. We focus on the modalities of eIF4E regulation at the biochemical and particularly structural level. In this instance, we describe not only the importance for the m7Gcap eIF4E interaction but also of recently discovered non-traditional RNA-eIF4E interactions as well as cap-independent activities of eIF4E. Further, we describe several distinct structural modalities used by the cell and some viruses to regulate or co-opt eIF4E, substantially extending the types of proteins that can regulate eIF4E from the traditional eIF4E-binding proteins (e.g. 4E-BP1 and eIF4G). Finally, we provide an overview of the results of targeting eIF4E activity in the clinic.
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The Eukaryotic Translation initiation factor eIF4E wears a "cap" for many occasions.
Translation (Austin Tex.), 2016Co-Authors: Katherine L. B. BordenAbstract:ABSTRACTThe Eukaryotic Translation initiation factor eIF4E plays important roles in controlling the composition of the proteome. Indeed, dysregulation of eIF4E is associated with poor prognosis cancers. The traditional view has been that eIF4E acts solely in Translation. However, over the last ∼25 years, eIF4E was found in the nucleus where it acts in mRNA export and in the last ∼10 years, eIF4E was found in cytoplasmic processing bodies (P-bodies) where it functions in mRNA sequestration and stability. The common biochemical thread for these activities is the ability of eIF4E to bind the 7-methylguanosine cap on the 5′ end of mRNAs. Recently, the possibility that eIF4E directly binds some mRNA elements independently of the cap has also been raised. Importantly, the effects of eIF4E are not genome-wide with a subset of transcripts targeted depending on the presence of specific mRNA elements and context-dependent regulatory factors. Indeed, eIF4E governs RNA regulons through co-regulating the expression of...
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The Eukaryotic Translation initiation factor eIF4E in the nucleus: taking the road less traveled
Immunological reviews, 2014Co-Authors: Michael J. Osborne, Katherine L. B. BordenAbstract:The Eukaryotic Translation initiation factor eIF4E is a potent oncogene. Although eIF4E has traditional roles in Translation initiation in the cytoplasm, it is also found in the nucleus, suggesting that it has activities beyond its role in protein synthesis. The road less traveled has been taken to study these nuclear activities and to understand their contribution to the oncogenic potential of eIF4E. The molecular features and biological pathways underpinning eIF4E's nuclear mRNA export are described. New classes of eIF4E regulators have been identified and their relevance to cancer shown. The studies presented here reveal the molecular, biophysical, and structural bases for eIF4E regulation. Finally, recent clinical work targeting eIF4E in acute myeloid leukemia patients with ribavirin is discussed. In summary, these findings provide a novel paradigm for eIF4E function and the molecular basis for targeting it in leukemia patients.
Ting Wei - One of the best experts on this subject based on the ideXlab platform.
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Binding of the Eukaryotic Translation elongation factor 1A with the 5’UTR of HIV-1 genomic RNA is important for reverse transcription
Virology journal, 2015Co-Authors: Ting Wei, Hongping Jin, Amanda Rose, Rui Wang, Min-hsuan Lin, Kirsten Spann, David HarrichAbstract:Background The cellular protein Eukaryotic Translation elongation factor 1A (eEF1A) binds to aminoacylated transfer RNAs and delivers them to the ribosome during Translation. eEF1A also binds to RNA secondary structures present in genomes of several RNA viruses and plays important roles in their replication. As a RNA binding protein, whether eEF1A can bind with HIV-1 genomic RNA has not been investigated and was the aim of the study.
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The Unexpected Roles of Eukaryotic Translation Elongation Factors in RNA Virus Replication and Pathogenesis
Microbiology and molecular biology reviews : MMBR, 2013Co-Authors: Ting Wei, Catherine M. Abbott, David HarrichAbstract:The prokaryotic Translation elongation factors were identified as essential cofactors for RNA-dependent RNA polymerase activity of the bacteriophage Qβ more than 40 years ago. A growing body of evidence now shows that Eukaryotic Translation elongation factors (eEFs), predominantly eEF1A, acting in partially characterized complexes sometimes involving additional eEFs, facilitate virus replication. The functions of eEF1A as a protein chaperone and an RNA- and actin-binding protein enable its "moonlighting" roles as a virus replication cofactor. A diverse group of viruses, from human immunodeficiency type 1 and West Nile virus to tomato bushy stunt virus, have adapted to use eEFs as cofactors for viral transcription, Translation, assembly, and pathogenesis. Here we review the mechanisms used by viral pathogens to usurp these abundant cellular proteins for their replication.
Shigeyuki Yokoyama - One of the best experts on this subject based on the ideXlab platform.
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crystal structure of Eukaryotic Translation initiation factor 2b
Nature, 2016Co-Authors: Kazuhiro Kashiwagi, Takuhiro Ito, Mari Takahashi, Madoka Nishimoto, Takuya B Hiyama, Toshiaki Higo, Takashi Umehara, Kensaku Sakamoto, Shigeyuki YokoyamaAbstract:Eukaryotic cells restrict protein synthesis under various stress conditions, by inhibiting the Eukaryotic Translation initiation factor 2B (eIF2B). eIF2B is the guanine nucleotide exchange factor for eIF2, a heterotrimeric G protein consisting of α-, β- and γ-subunits. eIF2B exchanges GDP for GTP on the γ-subunit of eIF2 (eIF2γ), and is inhibited by stress-induced phosphorylation of eIF2α. eIF2B is a heterodecameric complex of two copies each of the α-, β-, γ-, δ- and e-subunits; its α-, β- and δ-subunits constitute the regulatory subcomplex, while the γ- and e-subunits form the catalytic subcomplex. The three-dimensional structure of the entire eIF2B complex has not been determined. Here we present the crystal structure of Schizosaccharomyces pombe eIF2B with an unprecedented subunit arrangement, in which the α2β2δ2 hexameric regulatory subcomplex binds two γe dimeric catalytic subcomplexes on its opposite sides. A structure-based in vitro analysis by a surface-scanning site-directed photo-cross-linking method identified the eIF2α-binding and eIF2γ-binding interfaces, located far apart on the regulatory and catalytic subcomplexes, respectively. The eIF2γ-binding interface is located close to the conserved 'NF motif', which is important for nucleotide exchange. A structural model was constructed for the complex of eIF2B with phosphorylated eIF2α, which binds to eIF2B more strongly than the unphosphorylated form. These results indicate that the eIF2α phosphorylation generates the 'nonproductive' eIF2-eIF2B complex, which prevents nucleotide exchange on eIF2γ, and thus provide a structural framework for the eIF2B-mediated mechanism of stress-induced Translational control.
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Crystal structure of the Eukaryotic Translation initiation factor 2A from Schizosaccharomyces pombe.
Journal of structural and functional genomics, 2014Co-Authors: Kazuhiro Kashiwagi, Takuhiro Ito, Shigeyuki YokoyamaAbstract:The Eukaryotic Translation initiation factor 2A (eIF2A) was identified as a factor that stimulates the binding of methionylated initiator tRNA (Met-tRNAiMet) to the 40S ribosomal subunit, but its physiological role remains poorly defined. Recently, eIF2A was shown to be involved in unconventional Translation initiation from CUG codons and in viral protein synthesis under stress conditions where eIF2 is inactivated. We determined the crystal structure of the WD-repeat domain of Schizosaccharomyces pombe eIF2A at 2.5 A resolution. The structure adopts a novel nine-bladed β-propeller fold. In contrast to the usual β-propeller proteins, the central channel of the molecule has the narrower opening on the bottom of the protein and the wider opening on the top. Highly conserved residues are concentrated in the positively-charged top face, suggesting the importance of this face for interactions with nucleic acids or other initiation factors.