A5007998163- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- RNA Research and Splicing
- RNA regulation and disease
- Acute Lymphoblastic Leukemia research
- Genetics and Neurodevelopmental Disorders
- Polyamine Metabolism and Applications
- Endoplasmic Reticulum Stress and Disease
- Ubiquitin and proteasome pathways
- Plant and Fungal Interactions Research
- Advanced biosensing and bioanalysis techniques
- Chemical Synthesis and Analysis
- Acute Myeloid Leukemia Research
- Glycosylation and Glycoproteins Research
- Click Chemistry and Applications
- Protein Kinase Regulation and GTPase Signaling
- Cell death mechanisms and regulation
- Chronic Myeloid Leukemia Treatments
- Cancer-related gene regulation
- PI3K/AKT/mTOR signaling in cancer
- Ginger and Zingiberaceae research
- Autophagy in Disease and Therapy
- Monoclonal and Polyclonal Antibodies Research
- Chronic Lymphocytic Leukemia Research
- Viral Infectious Diseases and Gene Expression in Insects
Pennsylvania State University
2022-2024
National Institute of Technology Manipur
2024
Penn State Milton S. Hershey Medical Center
2023-2024
University of Kentucky
2024
Kansas State University
2011-2022
Institut thématique Génétique, génomique et bioinformatique
2013
Manhattan High School
2013
The University of Texas at Dallas
2005
Harvard University
2005
In the human genome, translation initiation from non-AUG codons plays an important role in various gene regulation programs. However, mechanisms regulating rate remain poorly understood. Here, we show that is nearly consistent under a fixed nucleotide context and insect cells. Yet, it ranges <1% to 100% compared AUG translation, depending on surrounding sequences, including Kozak, possibly additional contexts. Mechanistically, this range of controlled part, by eIF5-mimic protein (5MP). 5MP...
During eukaryotic translation initiation, eIF3 binds the solvent-accessible side of 40S ribosome and recruits gate-keeper protein eIF1 eIF5 to decoding center. This is largely mediated by N-terminal domain (NTD) eIF3c, which can be divided into three parts: 3c0, 3c1, 3c2. The part, strongly but only weakly ribosome-binding surface eIF1, whereas 3c1 3c2 form a stoichiometric complex with eIF1. contacts through Arg-53 Leu-96, while faces uS15/S13, anchor scanning pre-initiation (PIC). We...
ATF4 is a pro-oncogenic transcription factor whose translation activated by eIF2 phosphorylation through delayed re-initiation involving two uORFs in the mRNA leader. However, yeast, effect of can be mimicked eIF5 overexpression, which turns into translational inhibitor, thereby promoting GCN4, yeast equivalent. Furthermore, regulatory protein termed eIF5-mimic (5MP) bind and inhibit general translation. Here, we show that 5MP1 overexpression human cells leads to strong formation 5MP1:eIF2...
Eukaryotic initiation factor 4G (eIF4G) promotes mRNA recruitment to the ribosome by binding cap- and poly(A) tail-binding proteins eIF4E Pap1p. eIF4G also binds eIF4A at a distinct HEAT domain composed of five stacks antiparallel alpha-helices. The role in later steps initiation, such as scanning AUG recognition, has not been defined. Here we show that entire flanking residues Saccharomyces cerevisiae eIF4G2 are required for optimal interaction with recognition factors eIF5 eIF1. eIF1...
Eukaryotic translation initiation factor (eIF) 5 is crucial for the assembly of eukaryotic preinitiation complex. This activity mediated by ability its C-terminal HEAT domain to interact with eIF1, eIF2, and eIF3 in multifactor complex eIF4G 48S However, binding sites these factors on eIF5–C-terminal (CTD) have not been known. Here we present a homology model eIF5-CTD based eIF2Bε. We show that site eIF2β located surface area containing aromatic acidic residues (aromatic/acidic boxes), eIF1...
Eukaryotic initiation factor (eIF) 1 is a small protein (12 kDa) governing fidelity in translation initiation. It recruited to the 40 S subunit multifactor complex with Met-tRNA(i)(Met), eIF2, eIF3, and eIF5 binds near P-site. eIF1 release response start codon recognition an important signal produce 80 complex. Although ribosome-binding face of was identified, interfaces other preinitiation components their relevance function have not been determined. Exploiting solution structure yeast...
The translation factor eIF5 is an important partner of eIF2, directly modulating its function in several critical steps. First, binds eIF2/GTP/Met-tRNAiMet ternary complex (TC), promoting recruitment to 40S ribosomal subunits. Secondly, GTPase activating promotes eIF2 dissociation for subunit joining. Finally, GDP inhibition (GDI) activity can antagonize reactivation by competing with the guanine exchange (GEF), eIF2B. C-terminal domain (CTD) eIF5, a W2-type HEAT domain, mediates interaction...
Several proteasome-associated proteins regulate degradation by the 26 S proteasome using ubiquitin chains that mark most substrates for degradation. The protein Ecm29, however, has no ubiquitin-binding or modifying activity, and its direct effect on substrate is unclear. Here, we show Ecm29 acts as a inhibitor. Besides inhibiting proteolytic cleavage of peptide in vitro, it inhibits ubiquitin-dependent -independent vivo. Binding to induces closed conformation entry channel core particle....
Ribosomal stalk proteins recruit translation elongation GTPases to the factor-binding center of ribosome. Initiation factor 5B (eIF5B in eukaryotes and aIF5B archaea) is a universally conserved GTPase that promotes joining large small ribosomal subunits during initiation. Here we show binds C-terminal tail protein. In cocrystal structure, interaction occurs between hydrophobic amino acids pocket on surface GTP-binding domain (domain I) aIF5B. A substitution mutation altering yeast eIF5B...
eIF5-mimic protein (5MP) is a translational regulatory that binds the small ribosomal subunit and modulates its activity. 5MP proposed to reprogram non-AUG translation rates for oncogenes in cancer, but role controlling initiated synthesis of deleterious repeat-peptide products, such as FMRpolyG observed fragile-X-associated tremor ataxia syndrome (FXTAS), unknown. Here, we show can suppress both general repeat-associated (RAN) by common mechanism manner dependent on interaction with eIF3....
Eukaryotic initiation factor 1 (eIF1) is a low molecular weight critical for stringent AUG selection in eukaryotic translation. It recruited to the 43 S complex multifactor (MFC) with eIF2, eIF3, and eIF5 via multiple interactions MFC constituents. Here we show that FLAG epitope tagging of eIF1 at either terminus abolishes its vitro eIF2β but not eIF3c. Nevertheless, both forms FLAG-eIF1 fail bind eIF3 are incorporated into inefficiently vivo. C-terminal lethal; overexpression severely...
The integrity of eukaryotic translation initiation factor (eIF) interactions in ribosomal preinitiation complexes is critical for the proper regulation GCN4 mRNA response to amino acid availability.Increased phosphorylation eIF2 under starvation conditions leads a corresponding increase translation.The carboxyl-terminal domain (CTD) eIF5 (eIF5-CTD) has been identified as potential nucleation site complex assembly.To further characterize and delineate its role translational control, we...
During translation initiation in Saccharomyces cerevisiae, an Arg- and Ser-rich segment (RS1 domain) of eukaryotic factor 4G (eIF4G) the Lys-rich (K-boxes) eIF2β bind three common partners, eIF5, eIF1, mRNA. Here, we report that both these segments are involved mRNA recruitment AUG recognition by distinct mechanisms. First, eIF4G-RS1 interaction with eIF5 C-terminal domain (eIF5-CTD) directly links eIF4G to preinitiation complex (PIC) enhances binding. Second, eIF2β-K-boxes increase binding...
The carboxyl-terminal domain (CTD) of eukaryotic initiation factor (eIF) 5 interacts with eIF1, eIF2beta, and eIF3c, thereby mediating formation the multifactor complex (MFC), an important intermediate for 43 S preinitiation assembly. Here we demonstrate in vitro a nearly stoichiometric quaternary containing eIF1 minimal segments eIF5. In vivo, overexpression eIF2 tRNA(Met)(i) suppresses temperature-sensitive phenotype tif5-7A altering eIF5-CTD by increasing interaction mutant eIF5 mass...
Translation re-initiation provides the molecular basis for translational control of mammalian ATF4 and yeast GCN4 mediated by short upstream open reading (uORFs) in response to eIF2 phosphorylation. eIF4G is major adaptor subunit eIF4F that binds cap-binding eIF4E mRNA helicase eIF4A also required mammals. Here we show eIF4G2 mutations altering eIF4E- eIF4A-binding sites increase at impair recognition start codons uORF1 or uORF4 located after uORF1. The was partially suppressed increasing...
In eukaryotes, the 40 S ribosomal subunit serves as platform of initiation factor assembly, to place itself precisely on AUG start codon. Structural arrangement 18 rRNA determines overall shape subunit. Here, we present genetic evaluation yeast function using 10 point mutations altering polysome profile. All mutants reduce abundance mutant S, making it limiting for translation initiation. Two isolated mutations, G875A, core domain that binds eIF1 and eIF2, A1193U, changing h31 loop located...
The protein kinase Gcn2 is a central transducer of nutritional stress signaling important for adaptation by normal cells and the survival cancer cells. In response to nutrient deprivation, phosphorylates eIF2α, thereby repressing general translation while enhancing specific mRNAs with upstream ORFs (uORFs) situated in their 5'-leader regions. Here we performed genome-wide measurements mRNA during histidine starvation fission yeast Schizosaccharomyces pombe. Polysome analyses were combined...
In contrast to prokaryotes wherein GUG and UUG are permissive start codons, initiation frequencies from non-AUG codons generally low in eukaryotes, with CUG being considered as strongest. Here, we report that combined 5-cytosine methylation (5mC) pseudouridylation (Ψ) of near-cognate convert strongly favored over eukaryotic translation under a certain context. This prokaryotic-like preference is attributed enhanced NUG by Ψ the second base reduced 5mC first base. Molecular dynamics...
The 26S proteasome is a 2.5 MDa protease dedicated to the degradation of ubiquitinated proteins in eukaryotes. assembly this complex containing 66 polypeptides assisted by at least nine proteasome-specific chaperones. One these, Nas2, binds proteasomal AAA-ATPase subunit Rpt5. PDZ domain Nas2 C-terminal tail Rpt5; however, it does not require C-terminus Rpt5 for binding. Here, 1.15 Å resolution structure reported. This will provide basis further insights regarding and function assembly.
Abstract Background: Pre-B cell Acute lymphoblastic leukemia (B ALL) high risk (HR) subgroups continue to result in significant mortality and morbidity of pediatric oncology patients. T ALL is higher therapy has made less improvement than B with a rate poor outcomes. Novel treatment strategies are required overcome chemotherapy resistance improve mortality/morbidity for HR ALL. Leonurine bioactive alkaloid that naturally occurring only Herbra Leonuri which been used traditional herbal...