Ribosome Collisions and Translation Efficiency: Optimization by Codon Usage and mRNA Destabilization

Abstract

Individual mRNAs are translated by multiple ribosomes that initiate translation with an interval of a few seconds. The ribosome speed is codon dependent, and ribosome queuing has been suggested to explain specific data for translation of some mRNAs in vivo. By modeling the stochastic translation process as a traffic problem, we here analyze conditions and consequences of collisions and queuing. The model allowed us to determine the on-rate (0.8 to 1.1 initiations/s) and the time (1 s) the preceding ribosome occludes initiation for Escherichia coli lacZ mRNA in vivo. We find that ribosome collisions and queues are inevitable consequences of a stochastic translation mechanism that reduce the translation efficiency substantially on natural mRNAs. The cells minimize collisions by having its mRNAs being unstable and by a highly selected codon usage in the start of the mRNA. The cost of mRNA breakdown is offset by the concomitant increase in translation efficiency.

Translation by Ribosomes with mRNA Degradation: Exclusion Processes on Aging Tracks

“…Our results show that small degradation times can lead to significant effects on polysome statistics. These results are relevant for prokaryotic organisms such as E. coli where the degradation mechanism is simple and the average age of the mRNA is comparable to the time scale of translation, both of which can be of the order of a few minutes [15,[25][26][27]. In prokaryotes, mRNA translation begins before the completion of transcription.…”

“…where t s is defined in (15) and t L = L/v 1 . The averaging over age distribution according to (5) and (4) then leads to…”

“…Second, the ribosomes present on the mRNA at the moment of decapping are allowed to finish their translation [9,14]. While degradation of mRNA before completion of protein production looks like a wasteful process at first sight, it is also a control mechanism that enhances the efficiency of protein synthesis [15]. The effects of mRNA degradation have largely been overlooked in previous studies of dynamical models.…”

Evolutionary optimization of speed and accuracy of decoding on the ribosome

“…Following the recognition of the codon by the anticodon of aa-tRNA and GTP hydrolysis by EF-Tu, aa-tRNA is accommodated in the A site of the 50S subunit and takes part in peptide bond formation. The rate of protein elongation in bacteria is between 4 and 22 amino acids per second at 378C [1][2][3][4][5]; thus, a protein of an average length of 330 amino acids [6] is completed in about 10-80 s. The times required for initiation, termination and ribosome recycling (around 1 s each [3]) are short enough to make elongation rate-limiting for protein synthesis [7]. Translation of a particular codon depends on both the nature and abundance of the respective tRNAs, particularly on the non-random use of synonymous codons and the availability of the respective isoacceptor tRNAs [8].…”

“…Translation of a particular codon depends on both the nature and abundance of the respective tRNAs, particularly on the non-random use of synonymous codons and the availability of the respective isoacceptor tRNAs [8]. The overall rate of translation is limited by the codon-specific rates of cognate ternary complex delivery to the A site and is further attenuated by other factors, such as collisions between individual ribosomes in polysomes [3], controlled ribosome stalling (for a recent review, see [9]), or the cooperation between translating ribosomes and the RNA polymerase machinery [4,10].Estimations of error frequencies of translation range between 10 25 and 10 23 , depending on the type of measurement, concentrations and nature of tRNAs that perform misreading, and the mRNA context [11][12][13]. Different approaches were taken to measure these values.…”