Cristina Maracci

Marche Polytechnic University

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Marina V. Rodnina

Max Planck Institute for Multidisciplinary Sciences

N. Fischer

Max Planck Institute for Multidisciplinary Sciences

Daniel N. Wilson

Universität Hamburg

Prajwal Karki

Max Planck Institute for Biophysical Chemistry

Wolf Holtkamp

Paul Ehrlich Institut

Holger Stark

Heinrich Heine University Düsseldorf

Ralf Ficner

University of Göttingen

Lars V. Bock

Max Planck Institute for Multidisciplinary Sciences

Andrey L. Konevega

Peter the Great St. Petersburg Polytechnic University

Alena Paleskava

Petersburg Nuclear Physics Institute

Cooperative Institutions

Max Planck Institute for Biophysical Chemistry

Max Planck Society

Max Planck Institute for Multidisciplinary Sciences

University of Göttingen

Witten/Herdecke University

Ludwig-Maximilians-Universität München

Marche Polytechnic University

Center for Integrated Protein Science Munich

Universität Hamburg

Università di Camerino

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Control of the eIF4E activity: structural insights and pharmacological implications

Cellular and Molecular Life Sciences (2021)

Alice Romagnoli Mattia D’Agostino Chiara Ardiccioni Cristina Maracci Stefano Motta

Abstract The central role of eukaryotic translation initiation factor 4E (eIF4E) in controlling mRNA translation has been clearly assessed in the last decades. eIF4E function is essential for numerous physiological processes, such as protein synthesis, cellular growth and differentiation; dysregulation of its activity has been linked to ageing, cancer onset and progression and neurodevelopmental disorders, such as autism spectrum disorder (ASD) and Fragile X Syndrome (FXS). The interaction between eIF4E and the eukaryotic initiation factor 4G (eIF4G) is crucial for the assembly of the translational machinery, the initial step of mRNA translation. A well-characterized group of proteins, named 4E-binding proteins (4E-BPs), inhibits the eIF4E–eIF4G interaction by competing for the same binding site on the eIF4E surface. 4E-BPs and eIF4G share a single canonical motif for the interaction with a conserved hydrophobic patch of eIF4E. However, a second non-canonical and not conserved binding motif was recently detected for eIF4G and several 4E-BPs. Here, we review the structural features of the interaction between eIF4E and its molecular partners eIF4G and 4E-BPs, focusing on the implications of the recent structural and biochemical evidence for the development of new therapeutic strategies. The design of novel eIF4E-targeting molecules that inhibit translation might provide new avenues for the treatment of several conditions.

EIF4G

EIF4E

Eukaryotic translation

Eukaryotic initiation factor

Initiation factor

EIF4A1

Structural motif

10.1007/s00018-021-03938-z

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Citations (48)

Structure of the 70S ribosome with SECIS-mRNA and P-site tRNA (Initial complex, IC)

N. Fischer Piotr Neumann Lars V. Bock Cristina Maracci Z. Wang

T arm

Shine-Dalgarno sequence

Ribosomal binding site

10.2210/pdb5lza/pdbx

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Citations (0)

Translational recoding: canonical translation mechanisms reinterpreted

Nucleic Acids Research (2019)

Marina V. Rodnina Natalia Korniy Mariia Klimova Prajwal Karki Bee‐Zen Peng

Abstract During canonical translation, the ribosome moves along an mRNA from the start to the stop codon in exact steps of one codon at a time. The collinearity of the mRNA and the protein sequence is essential for the quality of the cellular proteome. Spontaneous errors in decoding or translocation are rare and result in a deficient protein. However, dedicated recoding signals in the mRNA can reprogram the ribosome to read the message in alternative ways. This review summarizes the recent advances in understanding the mechanisms of three types of recoding events: stop-codon readthrough, –1 ribosome frameshifting and translational bypassing. Recoding events provide insights into alternative modes of ribosome dynamics that are potentially applicable to other non-canonical modes of prokaryotic and eukaryotic translation.

Ribosome profiling

Stop codon

Translational frameshift

Nonsense-Mediated Decay

Shine-Dalgarno sequence

10.1093/nar/gkz783

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Citations (83)

Cryo-EM structure of a rotated E. coli 70S ribosome in complex with RF3-GDPCP, RF1(GAQ) and P/E-tRNA (State IV)

Michael Graf Paul Huter Cristina Maracci Miroslav Peterek Marina V. Rodnina

10.2210/pdb6gxo/pdbx

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Directional transition from initiation to elongation in bacterial translation

Nucleic Acids Research (2015)

Akanksha Goyal Riccardo Belardinelli Cristina Maracci Pohl Milón Marina V. Rodnina

The transition of the 30S initiation complex (IC) to the translating 70S ribosome after 50S subunit joining provides an important checkpoint for mRNA selection during translation in bacteria. Here, we study the timing and control of reactions that occur during 70S IC formation by rapid kinetic techniques, using a toolbox of fluorescence-labeled translation components. We present a kinetic model based on global fitting of time courses obtained with eight different reporters at increasing concentrations of 50S subunits. IF1 and IF3 together affect the kinetics of subunit joining, but do not alter the elemental rates of subsequent steps of 70S IC maturation. After 50S subunit joining, IF2-dependent reactions take place independent of the presence of IF1 or IF3. GTP hydrolysis triggers the efficient dissociation of fMet-tRNAfMet from IF2 and promotes the dissociation of IF2 and IF1 from the 70S IC, but does not affect IF3. The presence of non-hydrolyzable GTP analogs shifts the equilibrium towards a stable 70S–mRNA–IF1–IF2–fMet-tRNAfMet complex. Our kinetic analysis reveals the molecular choreography of the late stages in translation initiation.

Eukaryotic initiation factor

Eukaryotic translation

Initiation factor

eIF2

10.1093/nar/gkv869

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Citations (55)

Structure of the P+9 ArfB-ribosome complex with P/E hybrid tRNA in the post-hydrolysis state

Kwok-Ho Chan V. Petrychenko Claudia Mueller Cristina Maracci Wolf Holtkamp

10.2210/pdb6yst/pdb

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Dynamics of ribosomes and release factors during translation termination inE. coli

bioRxiv (Cold Spring Harbor Laboratory) (2018)

Sarah Adio Heena Sharma Tamara Senyushkina Prajwal Karki Cristina Maracci

Abstract Release factors RF1 and RF2 promote hydrolysis of peptidyl-tRNA during translation termination. The GTPase RF3 promotes recycling of RF1 and RF2. Using single molecule FRET together with ensemble kinetics, we show that ribosome termination complexes that carry two factors, RF1–RF3 or RF2–RF3, are dynamic and fluctuate between non-rotated and rotated states, while each factor alone has its distinct signature on the ribosome dynamics and conformation. Dissociation of RF1 depends on peptide release and the presence of RF3, whereas RF2 can dissociate spontaneously. RF3 binds in the GTP-bound state and can rapidly dissociate without GTP hydrolysis from termination complex carrying RF1. GTP cleavage helps RF3 release from ribosomes stalled in the rotated state in the absence of RF1. Our data suggest how the stochastic assembly of the ribosome–RF1–RF3–GTP complex, peptide release, and ribosome fluctuations promote termination of protein synthesis and recycling of the release factors.

Release factor

A-site

Cleavage (geology)

10.1101/243485

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Activities of the peptidyl transferase center of ribosomes lacking protein L27

RNA (2015)

Cristina Maracci Ingo Wohlgemuth Marina V. Rodnina

The ribosome is the molecular machine responsible for protein synthesis in all living organisms. Its catalytic core, the peptidyl transferase center (PTC), is built of rRNA, although several proteins reach close to the inner rRNA shell. In the Escherichia coli ribosome, the flexible N-terminal tail of the ribosomal protein L27 contacts the A- and P-site tRNA. Based on computer simulations of the PTC and on previous biochemical evidence, the N-terminal α-amino group of L27 was suggested to take part in the peptidyl-transfer reaction. However, the contribution of this group to catalysis has not been tested experimentally. Here we investigate the role of L27 in peptide-bond formation using fast kinetics approaches. We show that the rate of peptide-bond formation at physiological pH, both with aminoacyl-tRNA or with the substrate analog puromycin, is independent of the presence of L27; furthermore, translation of natural mRNAs is only marginally affected in the absence of L27. The pH dependence of the puromycin reaction is unaltered in the absence of L27, indicating that the N-terminal α-amine is not the ionizing group taking part in catalysis. Likewise, L27 is not required for the peptidyl-tRNA hydrolysis during termination. Thus, apart from the known effect on subunit association, which most likely explains the phenotype of the deletion strains, L27 does not appear to be a key player in the core mechanism of peptide-bond formation on the ribosome.

Peptidyl transferase

Puromycin

Peptide bond

Eukaryotic Ribosome

50S

P-site

10.1261/rna.053330.115

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Citations (19)

Tissue-specific regulation of translational readthrough tunes functions of the traffic jam transcription factor

Nucleic Acids Research (2021)

Prajwal Karki Travis D. Carney Cristina Maracci Andriy S. Yatsenko Halyna R. Shcherbata

Translational readthrough (TR) occurs when the ribosome decodes a stop codon as a sense codon, resulting in two protein isoforms synthesized from the same mRNA. TR has been identified in several eukaryotic organisms; however, its biological significance and mechanism remain unclear. Here, we quantify TR of several candidate genes in Drosophila melanogaster and characterize the regulation of TR in the large Maf transcription factor Traffic jam (Tj). Using CRISPR/Cas9-generated mutant flies, we show that the TR-generated Tj isoform is expressed in a subset of neural cells of the central nervous system and is excluded from the somatic cells of gonads. Control of TR in Tj is critical for preservation of neuronal integrity and maintenance of reproductive health. The tissue-specific distribution of a release factor splice variant, eRF1H, plays a critical role in modulating differential TR of leaky stop codon contexts. Fine-tuning of gene regulatory functions of transcription factors by TR provides a potential mechanism for cell-specific regulation of gene expression.

10.1093/nar/gkab1189

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Citations (18)

Structure of SelB-Sec-tRNASec bound to the 70S ribosome in the codon reading state (CR)

N. Fischer Piotr Neumann Lars V. Bock Cristina Maracci Z. Wang

Selenocysteine

10.2210/pdb5lzc/pdbx

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Citations (0)