Arginine Methylation Regulates Ribosome CAR Function

Scopino, Kristen; Dalgarno, Carol; Nachmanoff, Clara; Krizanc, Daniel; Thayer, Kelly M.; Weir, Michael P.

doi:10.3390/ijms22031335

Cited by 9 publications

(30 citation statements)

References 55 publications

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“…MD simulations with the AMBER suite [31] were used to assess CAR interactions with the +1 codon as described previously [18,19]. We used a 494-residue subsystem of the ribosome centered around C1054 of the CAR interface that included the A-site codon and +1 codon of the mRNA, and an anticodon region of the tRNA.…”

Section: Car/mrna H-bonding Is Sequence Dependentmentioning

confidence: 99%

“…We used a 494-residue subsystem of the ribosome centered around C1054 of the CAR interface that included the A-site codon and +1 codon of the mRNA, and an anticodon region of the tRNA. The residues at the edges of the subsystem were restrained to their initial coordinates (onion shell; [18,19]) to conform to translocation stage II (PDB ID 5JUP; [20]), the stage that exhibits the most robust CAR/+1 codon H-bond interactions.…”

Section: Car/mrna H-bonding Is Sequence Dependentmentioning

confidence: 99%

“…Stacking interactions can make important contributions to the stabilities of RNA structures [34]. In MD simulations of the +1 GCU ribosome subsystem, as discussed above, the CAR interaction surface is anchored to the tRNA nt34 through base stacking with C1054, and the CAR surface itself displays stacking interactions between its adjacent residues: base stacking between C1054/A1196 and cation-pi stacking between A1196/R146 [18,19]. We were curious whether +1 codons with weaker H-bonding to CAR influenced the CAR anchoring or stacking interactions.…”

Section: Mrna Interactions Modulate Car Integrity and Anchoringmentioning

confidence: 99%

“…Stacking between pairs of residues was analyzed by measuring the distance between the centers of mass (COM) of adjacent resides as described previously [18,19]. COM distances were calculated for four different stacking pairs: tRNA nt35 to nt34, tRNA nt34 to C1054, C1054 to A1196, and A1196 to R146.…”

Section: Mrna Interactions Modulate Car Integrity and Anchoringmentioning

confidence: 99%

“…Using molecular dynamics (MD) methods, we recently identified a ribosome interaction surface termed CAR (Fig 1 ) that we hypothesize provides a layer of translation regulation under stress conditions through production of ribosomes with an altered version of the CAR surface [17][18][19]. Protein translation requires efficient translocation of mRNA codons through the decoding center aminoacyl (A) site where the codon base pairs with the anticodon of the tRNA that brings in the next amino acid for the growing newly synthesized protein.…”

Section: Introductionmentioning

confidence: 99%

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The CAR mRNA-Interaction Surface is a Zipper Extension of the Ribosome A Site

Dalgarno

Scopino

Raval

et al. 2022

Preprint

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The ribosome CAR interaction surface behaves like an extension of the decoding center A site and has H-bond interactions with the +1 codon that is next in line to enter the A site. Through molecular dynamics simulations, we investigated the codon sequence specificity of this CAR-mRNA interaction and discovered a strong preference for GCN codons, suggesting that there may be a sequence-dependent layer of translational regulation dependent on the CAR interaction surface. Dissection of the CAR-mRNA interaction through nucleotide substitution experiments showed that the first nucleotide of the +1 codon dominates over the second nucleotide position, consistent with an energetically favorable zipper-like activity that emanates from the A site through the CAR-mRNA interface. The +1 codon/CAR interaction is also affected by the identity of nucleotide 3 of +1 GCN codons which influences the stacking of G and C. Clustering analysis suggests that the A site decoding center adopts different neighborhood substates that depend on the identity of the +1 codon.

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Section: Car/mrna H-bonding Is Sequence Dependentmentioning

confidence: 99%

Section: Car/mrna H-bonding Is Sequence Dependentmentioning

confidence: 99%

Section: Mrna Interactions Modulate Car Integrity and Anchoringmentioning

confidence: 99%

Section: Mrna Interactions Modulate Car Integrity and Anchoringmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The CAR mRNA-Interaction Surface is a Zipper Extension of the Ribosome A Site

Dalgarno

Scopino

Raval

et al. 2022

Preprint

Self Cite

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GNN codon adjacency regulates protein translation

Sun,

Hwang,

Sakkas

et al. 2024

Preprint

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The central dogma treats the ribosome as a molecular machine that reads one mRNA codon at a time as it adds each amino acid to its growing peptide chain. However, this and previous studies suggest that ribosomes actually perceive pairs of adjacent codons as they take three-nucleotide steps along the mRNA. We examined GNN codons which we find are surprisingly overrepresented in eukaryote protein-coding open reading frames (ORFs), especially immediately after NNU codons. Ribosome profiling experiments in yeast revealed that ribosomes with NNU at their aminoacyl (A) site have particularly elevated densities when NNU is immediately followed (3') by a GNN codon, indicating slower mRNA threading of the NNU codon from the ribosome's A to peptidyl (P) sites. Moreover, if the assessment was limited to ribosomes that have only recently arrived at the next codon, by examining 21-nucleotide ribosome footprints (21-nt RFPs), elevated densities were observed for multiple codon classes when followed by GNN. This striking translation slowdown at adjacent 5'-NNN GNN codon pairs is likely mediated in part by the ribosome's CAR surface which acts as an extension of the A-site tRNA anticodon during ribosome translocation and interacts through hydrogen bonding and pi stacking with the GNN codon. The functional consequences of 5'-NNN GNN codon adjacency are expected to influence the evolution of protein coding sequences.

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