Peptidyl transferase center decompaction and structural constraints during early protein elongation on the ribosome

Bin Jia,Jean Lehmann,Tianlong Wang

doi:10.1038/s41598-021-02985-7

Abstract

Peptide bond formation on the ribosome requires that aminoacyl-tRNAs and peptidyl-tRNAs are properly positioned on the A site and the P site of the peptidyl transferase center (PTC) so that nucleophilic attack can occur. Here we analyse some constraints associated with the induced-fit mechanism of the PTC, that promotes this positioning through a compaction around the aminoacyl ester orchestrated by U2506. The physical basis of PTC decompaction, that allows the elongated peptidyl-tRNA to free itself from that state and move to the P site of the PTC, is still unclear. From thermodynamics considerations and an analysis of published ribosome structures, the present work highlights the rational of this mechanism, in which the free-energy released by the new peptide bond is used to kick U2506 away from the reaction center. Furthermore, we show the evidence that decompaction is impaired when the nascent peptide is not yet anchored inside the exit tunnel, which may contribute to explain why the first rounds of elongation are inefficient, an issue that has attracted much interest for about two decades. Results in this field are examined in the light of the present analysis and a physico-chemical correlation in the genetic code, which suggest that elementary constraints associated with the size of the side-chain of the amino acids penalize early elongation events.

Highlights

Peptide bond formation on the ribosome requires that aminoacyl-tRNAs and peptidyl-tRNAs are properly positioned on the A site and the P site of the peptidyl transferase center (PTC) so that nucleophilic attack can occur
Based on a survey and examination of ribosome structures complexed with various arrest peptidyl-tRNA and peptidyl-tRNA analogs retrieved from the pdb database, and from free-energy estimates, the present work shows that some of the free-energy released by the reaction of peptide bond formation is used to decompact the PTC, which allows the peptidyl-tRNA to freely move to the P site
Upon binding of the CCA 3ʹ end of an incoming tRNA on the A site, the G2583-U2506 wobble base pair that usually keeps U2506 away from the reaction center breaks, forcing U2506 to adopt a conformation jamming the Cα of the aminoacyl ester against the A76 2ʹOH of the P site tRNA (Fig. 1A)

Summary

Introduction

Peptide bond formation on the ribosome requires that aminoacyl-tRNAs and peptidyl-tRNAs are properly positioned on the A site and the P site of the peptidyl transferase center (PTC) so that nucleophilic attack can occur. We show the evidence that decompaction is impaired when the nascent peptide is not yet anchored inside the exit tunnel, which may contribute to explain why the first rounds of elongation are inefficient, an issue that has attracted much interest for about two decades. Results in this field are examined in the light of the present analysis and a physico-chemical correlation in the genetic code, which suggest that elementary constraints associated with the size of the side-chain of the amino acids penalize early elongation events. A76 P site various effects of the amino acids on translational efficiency become essentially uniform starting from position 7, suggesting that nascent proteins are anchored inside the exit tunnel from that size

Methods

Results

Conclusion