scholarly journals Conformational ordering of intrinsically disordered peptides for targeting translation initiation

2020 ◽  
Author(s):  
Christopher J Brown ◽  
Chandra S Verma ◽  
David P Lane ◽  
Dilraj Lama
Keyword(s):  
Translation Initiation ◽  
Protein Interactions ◽  
Bound State ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Structural Reorganization ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Conformational Ordering ◽  
Natural Amino Acids

AbstractIntrinsically disordered regions (IDRs) in proteins can regulate their activity by facilitating protein-protein interactions (PPIs) as exemplified in the recruitment of the eukaryotic translation initiation factor 4E (eIF4E) protein by the protein eIF4G. Deregulation of this PPI module is central to a broad spectrum of cancer related malignancies and its targeted inhibition through bioactive peptides is a promising strategy for therapeutic intervention. We have employed a structure-guided approach to rationally develop peptide derivatives from the intrinsically disordered eIF4G scaffold by incorporating non-natural amino acids that facilitates disorder-to-order transition. The conformational heterogeneity of these peptides and the degree of structural reorganization required to adopt the optimum mode of interaction with eIF4E underscores their differential binding affinities. The presence of a pre-structured local helical element in the ensemble of structures was instrumental in the efficient docking of the peptides on to the protein surface. These insights were exploited to further design features into the peptide to propagate bound-state conformations in solution which resulted in the generation of a potent eIF4E binder. The study illustrates the molecular basis of eIF4E recognition by a disordered epitope from eIF4G and its modulation to generate peptides that can potentially attenuate translation initiation in oncology.

scholarly journals Molecular Structure and Functional Elucidation of IF-3 Protein of Chloroflexus Aurantiacus Involved in Protein Biosynthesis: An In-Silico Approach

2021 ◽  
Author(s):  
Abu Saim Mohammad Saikat
Keyword(s):  
Translation Initiation ◽  
Protein Interactions ◽  
In Silico ◽  
Tertiary Structure ◽  
Protein Biosynthesis ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Chloroflexus Aurantiacus ◽  
Protein Protein Interactions ◽  
Functional Interpretation

<p><i>Chloroflexus aurantiacus</i> is a thermophilic bacterium that produces a multitude of proteins within its genome. Bioinformatics strategies can facilitate comprehending this organism through functional and structural interpretation assessments. This study aimed to allocate the structure and function through an in-silico approach required for bacterial protein biosynthesis. This in-silico viewpoint provides copious properties, including the physicochemical properties, subcellular location, three-dimensional structure, protein-protein interactions, and functional elucidation of the protein (WP_012256288.1). The STRING program is utilized for the explication of protein-protein interactions. The in-silico investigation documented the protein's hydrophilic nature with predominantly alpha (α) helices in its secondary structure. The tertiary-structure model of the protein has been shown to exhibit reasonably high consistency based on various quality assessment methods. The functional interpretation suggested that the protein can act as a translation initiation factor, a protein required for translation and protein biosynthesis. Protein-protein interactions also demonstrated high credence that the protein interconnected with 30S ribosomal subunit involved in protein synthesis. This study is bioinformatically examined that the protein (WP_012256288.1) is affiliated in protein biosynthesis as a translation initiation factor IF-3 of <i>C. aurantiacus</i>. </p> <p> </p>

scholarly journals Structural and Functional Elucidation of IF-3 Protein of Chloroflexus aurantiacus Involved in Protein Biosynthesis: An In-Silico Approach

2021 ◽  
Author(s):  
Abu Saim Mohammad Saikat ◽  
Md. Ekhlas Uddin ◽  
Tasnim Ahmad ◽  
Shahriar Mahmud ◽  
Md. Abu Sayeed Imran ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Protein Interactions ◽  
In Silico ◽  
Tertiary Structure ◽  
Protein Biosynthesis ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Chloroflexus Aurantiacus ◽  
Protein Protein Interactions ◽  
Functional Interpretation

<p>Chloroflexus aurantiacus is a thermophilic bacterium that produces a multitude of proteins<br>within its genome. Bioinformatics strategies can facilitate comprehending this organism through<br>functional and structural interpretation assessments.This study aimed to allocate the structure and<br>function through an in-silico approach required for bacterial protein biosynthesis. This in-silico<br>viewpoint provides copious properties, including the physicochemical properties, subcellular location,<br>three-dimensional structure, protein-protein interactions, and functional elucidation of the protein<br>(WP_012256288.1). The STRING program is utilized for the explication of protein-protein<br>interactions. The in-silico investigation documented the protein's hydrophilic nature with<br>predominantly alpha (α) helices in its secondary structure.The tertiary-structure model of the protein<br>has been shown to exhibit reasonably high consistency based on various quality assessment<br>methods.The functional interpretation suggested that the protein can act as a translation initiation<br>factor, a protein required for translation and protein biosynthesis. Protein-protein interactions also<br>demonstrated high credence that the protein interconnected with 30S ribosomal subunit involved in<br>protein synthesis. This study is bioinformatically examined that the protein (WP_012256288.1) is<br>affiliated in protein biosynthesis as a translation initiation factor IF-3 of C. aurantiacus. <br><br></p>

The third structural switch in the archaeal translation initiation factor 2 (aIF2) molecule and its possible role in the initiation of GTP hydrolysis and the removal of aIF2 from the ribosome

2019 ◽  
Vol 75 (4) ◽  
pp. 392-399
Author(s):  
Oleg Nikonov ◽  
Olesya Kravchenko ◽  
Natalia Nevskaya ◽  
Elena Stolboushkina ◽  
Maria Garber ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Active Form ◽  
Bound State ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Γ Subunit ◽  
Initiation Factor 2 ◽  
Crystallization Solution ◽  
Translation Initiation Factor 2

The structure of the γ subunit of archaeal translation initiation factor 2 (aIF2) fromSulfolobus solfataricus(SsoIF2γ) was determined in complex with GDPCP (a GTP analog). Crystals were obtained in the absence of magnesium ions in the crystallization solution. They belonged to space groupP1, with five molecules in the unit cell. Four of these molecules are related in pairs by a common noncrystallographic twofold symmetry axis, while the fifth has no symmetry equivalent. Analysis of the structure and its comparison with other known aIF2 γ-subunit structures in the GTP-bound state show that (i) the magnesium ion is necessary for the formation and the maintenance of the active form of SsoIF2γ and (ii) in addition to the two previously known structural switches 1 and 2, eukaryotic translation initiation factor 2 (eIF2) and aIF2 molecules have another flexible region (switch 3), the function of which may consist of initiation of the hydrolysis of GTP and the removal of e/aIF2 from the ribosome after codon–anticodon recognition.

scholarly journals Structure determination of protein-peptide complexes from NMR chemical shift data using MELD.

2022 ◽  
Author(s):  
Arup Mondal ◽  
G.V.T. Swapna ◽  
Jingzhou Hao ◽  
LiChung Ma ◽  
Monica J. Roth ◽  
...  
Keyword(s):  
Chemical Shift ◽  
Protein Interactions ◽  
Protein Complexes ◽  
Bound State ◽  
Nmr Chemical Shift ◽  
Modeling Tools ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Chemical Shift Data ◽  
Shift Data

Intrinsically disordered regions of proteins often mediate important protein-protein interactions. However, the folding upon binding nature of many polypeptide-protein interactions limits the ability of modeling tools to predict structures of such complexes. To address this problem, we have taken a tandem approach combining NMR chemical shift data and molecular simulations to determine structures of peptide-protein complexes. Here, we demonstrate this approach for polypeptide com-plexes formed with the extraterminal (ET) domain of bromo and extraterminal domain (BET) proteins, which exhibit a high degree of binding plasticity. This system is particularly challenging as the binding process includes allosteric changes across the ET receptor upon binding, and the polypeptide binding partners can form different conformations (e.g., helices and hair-pins) in the complex. In a blind study, the new approach successfully modeled bound-state conformations and binding pos-es, using only backbone chemical shift data, in excellent agreement with experimentally-determined structures. The approach also predicts relative binding affinities of different peptides. This hybrid MELD-NMR approach provides a powerful new tool for structural analysis of protein-polypeptide complexes in the low NMR information content regime, which can be used successfully for flexible systems where one polypeptide binding partner folds upon complex formation.

scholarly journals Spectroscopic Investigation of the Kinetic Mechanism Involved in the Association of Potyviral VPg with the Host Plant Translation Initiation Factor eIF4E

2020 ◽  
Vol 21 (16) ◽  
pp. 5618
Author(s):  
Jocelyne Walter ◽  
Amandine Barra ◽  
Justine Charon ◽  
Geneviève Tavert-Roudet ◽  
Thierry Michon
Keyword(s):  
Amino Acids ◽  
Translation Initiation ◽  
Plant Resistance ◽  
Kinetic Mechanism ◽  
Single Step ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Intrinsically Disordered ◽  
Resistance Breaking ◽  
Central Helix

The infectious cycle of potyviruses requires the formation of a complex between the viral genome-linked protein VPg and the host eukaryotic translation initiation factor 4E, eIF4E. Mutations associated with plant resistance to potyviruses were previously mapped at the eIF4E surface, while on the virus side, mutations leading to plant resistance breaking were identified within the VPg. In the present study, fluorescence spectroscopy was used to probe the contribution of the VPg intrinsically disordered region bearing amino acids determinant of the resistance breaking, to the VPg–eIF4E binding mechanism. Synthetic peptides encompassing the VPg88–120 central region were found to tightly bind to eIF4E. Fluorescence energy transfer experiments show that, upon binding to eIF4E, the N and C termini of the VPg88–111 fragment move closer to one another, at a distance compatible with a α-helix folding. When the VPg112–120 region, which contains amino acids associated with resistance breakdown, is appended to VPg88–111, the complex formation with eIF4E switches from a single-step to a two-step kinetic model. This study revisits a recent investigation of the VPg–eIF4E complex by specifying the contribution of the VPg central helix and its appended disordered region to VPg association with eIF4E.

scholarly journals A specific eIF4A paralog facilitates LARP1-mediated translation repression during mTORC1 inhibition

2021 ◽  
Author(s):  
Yuichi Shichino ◽  
Mari Mito ◽  
Kazuhiro Kashiwagi ◽  
Mari Takahashi ◽  
Takuhiro Ito ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Protein Interactions ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Ribosome Profiling ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Mtor Inhibition ◽  
Translation Repression

AbstractEukaryotic translation initiation factor (eIF) 4A — a DEAD-box RNA-binding protein — plays an essential role in translation initiation. Two mammalian eIF4A paralogs, eIF4A1 and eIF4A2, have been assumed to be redundant because of their high homology, and the difference in their functions has been poorly understood. Here, we show that eIF4A1, but not eIF4A2, enhances translational repression during the inhibition of mechanistic target of rapamycin complex 1 (mTORC1), an essential kinase complex controlling cell proliferation. RNA-immunoprecipitation sequencing (RIP-Seq) of the two eIF4A paralogs revealed that eIF4A1 preferentially binds to mRNAs containing terminal oligopyrimidine (TOP) motifs, whose translation is rapidly repressed upon mTOR inhibition. This biased interaction depends on a La-related RNA-binding protein, LARP1. Ribosome profiling revealed that the deletion of EIF4A1, but not EIF4A2, rendered the translation of TOP mRNAs resistant to mTOR inactivation. Moreover, eIF4A1 enhances the affinity between TOP mRNAs and LARP1 and thus ensures stronger translation repression upon mTORC1 inhibition. Our data show that the distinct protein interactions of these highly homologous translation factor paralogs shape protein synthesis during mTORC1 inhibition and provide a unique example of the repressive role of a universal translation activator.

scholarly journals Molecular Structure and Functional Elucidation of IF-3 Protein of Chloroflexus Aurantiacus Involved in Protein Biosynthesis: An In-Silico Approach

2021 ◽  
Author(s):  
Abu Saim Mohammad Saikat
Keyword(s):  
Translation Initiation ◽  
Protein Interactions ◽  
In Silico ◽  
Tertiary Structure ◽  
Protein Biosynthesis ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Chloroflexus Aurantiacus ◽  
Protein Protein Interactions ◽  
Functional Interpretation

<p><i>Chloroflexus aurantiacus</i> is a thermophilic bacterium that produces a multitude of proteins within its genome. Bioinformatics strategies can facilitate comprehending this organism through functional and structural interpretation assessments. This study aimed to allocate the structure and function through an in-silico approach required for bacterial protein biosynthesis. This in-silico viewpoint provides copious properties, including the physicochemical properties, subcellular location, three-dimensional structure, protein-protein interactions, and functional elucidation of the protein (WP_012256288.1). The STRING program is utilized for the explication of protein-protein interactions. The in-silico investigation documented the protein's hydrophilic nature with predominantly alpha (α) helices in its secondary structure. The tertiary-structure model of the protein has been shown to exhibit reasonably high consistency based on various quality assessment methods. The functional interpretation suggested that the protein can act as a translation initiation factor, a protein required for translation and protein biosynthesis. Protein-protein interactions also demonstrated high credence that the protein interconnected with 30S ribosomal subunit involved in protein synthesis. This study is bioinformatically examined that the protein (WP_012256288.1) is affiliated in protein biosynthesis as a translation initiation factor IF-3 of <i>C. aurantiacus</i>. </p> <p> </p>

scholarly journals Hydrodynamic Behavior of the Intrinsically Disordered Potyvirus Protein VPg, of the Translation Initiation Factor eIF4E and of their Binary Complex

2019 ◽  
Vol 20 (7) ◽  
pp. 1794 ◽  
Author(s):  
Jocelyne Walter ◽  
Amandine Barra ◽  
Bénédicte Doublet ◽  
Nicolas Céré ◽  
Justine Charon ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Molten Globule ◽  
Translation Initiation Factor ◽  
Size Exclusion ◽  
Initiation Factor ◽  
Binary Complex ◽  
Hydrodynamic Behavior ◽  
Hydrodynamic Properties ◽  
Intrinsically Disordered ◽  
His Tag

Protein intrinsic disorder is involved in many biological processes and good experimental models are valuable to investigate its functions. The potyvirus genome-linked protein, VPg, displays many features of an intrinsically disordered protein. The virus cycle requires the formation of a complex between VPg and eIF4E, one of the host translation initiation factors. An in-depth characterization of the hydrodynamic properties of VPg, eIF4E, and of their binary complex VPg-eIF4E was carried out. Two complementary experimental approaches, size-exclusion chromatography and fluorescence anisotropy, which is more resolving and revealed especially suitable when protein concentration is the limiting factor, allowed to estimate monomers compaction upon complex formation. VPg possesses a high degree of hydration which is in agreement with its classification as a partially folded protein in between a molten and pre-molten globule. The natively disordered first 46 amino acids of eIF4E contribute to modulate the protein hydrodynamic properties. The addition of an N-ter His tag decreased the conformational entropy of this intrinsically disordered region. A comparative study between the two tagged and untagged proteins revealed the His tag contribution to proteins hydrodynamic behavior.

scholarly journals Structural and Functional Elucidation of IF-3 Protein of Chloroflexus aurantiacus Involved in Protein Biosynthesis: An In Silico Approach

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Abu Saim Mohammad Saikat ◽  
Md. Ekhlas Uddin ◽  
Tasnim Ahmad ◽  
Shahriar Mahmud ◽  
Md. Abu Sayeed Imran ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Protein Interactions ◽  
In Silico ◽  
Tertiary Structure ◽  
Protein Biosynthesis ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Chloroflexus Aurantiacus ◽  
Protein Protein Interactions ◽  
Functional Interpretation

Chloroflexus aurantiacus is a thermophilic bacterium that produces a multitude of proteins within its genome. Bioinformatics strategies can facilitate comprehending this organism through functional and structural interpretation assessments. This study is aimed at allocating the structure and function through an in silico approach required for bacterial protein biosynthesis. This in silico viewpoint provides copious properties, including the physicochemical properties, subcellular location, three-dimensional structure, protein-protein interactions, and functional elucidation of the protein (WP_012256288.1). The STRING program is utilized for the explication of protein-protein interactions. The in silico investigation documented the protein’s hydrophilic nature with predominantly alpha (α) helices in its secondary structure. The tertiary-structure model of the protein has been shown to exhibit reasonably high consistency based on various quality assessment methods. The functional interpretation suggested that the protein can act as a translation initiation factor, a protein required for translation and protein biosynthesis. Protein-protein interactions also demonstrated high credence that the protein interconnected with 30S ribosomal subunit involved in protein synthesis. This study bioinformatically examined that the protein (WP_012256288.1) is affiliated in protein biosynthesis as a translation initiation factor IF-3 of C. aurantiacus.

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