Dependence of Protein Synthesis on TRNA Concentrations

Abstract

During protein synthesis, a ribosome moves along a messenger RNA (mRNA) and translates it codon by codon by binding and recognizing the appropriate aminoacylated transfer RNAs (aa-tRNAs). We developed a stochastic theory for this process of translation elongation and determined the dependence of elongation speed on codon sequence as well as on the concentrations of ribosomes and and aa-tRNAs. We find that the variation of a single aa-tRNA concentration leads to three distinct regimes of protein synthesis. In the depletion regime characterized by low aa-tRNA concentrations, the ribosomal peptide synthesis rate follows a general Michaelis-Menten law. Furthermore, we find a remarkably broad range of intermediate aa-tRNA concentrations, for which translation is very stable and the ribosomal peptide synthesis rate is essentially constant. For large concentrations, crowding of aa-tRNAs and the competition between non-cognate and cognate aa-tRNAs strongly impede protein synthesis. Our results provide new insights into the process of protein synthesis and the role of aa-tRNA concentrations therein. Knowing the influence of aa-tRNA concentrations on translation is pivotal to further progress in understanding and controlling protein synthesis, e.g., in tRNA over-expressing cancer cells as well as in cell-free expression systems and organisms bioengineered for high yield protein production.