Mechanical Forces and Their Effect on the Ribosome and Protein Translation Machinery

Abstract

Mechanical forces acting on biological systems, at both the macroscopic and microscopic levels, play an important part in shaping cellular phenotypes. There is a growing realization that biomolecules that respond to force directly applied to them, or via mechano-sensitive signalling pathways, can produce profound changes to not only transcriptional pathways, but also in protein translation. Forces naturally occurring at the molecular level can impact the rate at which the bacterial ribosome translates messenger RNA (mRNA) transcripts and influence processes such as co-translational folding of a nascent protein as it exits the ribosome. In eukaryotes, force can also be transduced at the cellular level by the cytoskeleton, the cell's internal filamentous network. The cytoskeleton closely associates with components of the translational machinery such as ribosomes and elongation factors and, as such, is a crucial determinant of localized protein translation. In this review we will give (1) a brief overview of protein translation in bacteria and eukaryotes and then discuss (2) how mechanical forces are directly involved with ribosomes during active protein synthesis and (3) how eukaryotic ribosomes and other protein translation machinery intimately associates with the mechanosensitive cytoskeleton network.

Keywords: forces; protein translation; ribosome.

Figure 1

Mechanics in protein translation. (A) Schematic of role of forces in prokaryotic protein translation. (i) Forces are generated during the ratchet motion—a molecular motion that moves the tRNA and mRNA so that the next codon in sequence can be read. (ii) Force is required to unwind downstream mRNA hairpins, that act as a mechano-translocation barrier, and allow ribosomes to decode the codon sequence hidden within. (iii) Tugging forces also occur on the polypeptide chain as it folds which are propagated back to the ribosomal machinery; these forces help overcome translational pauses. (B) In eukaryotic cells, forces can be generated internally, i.e., by the dynamic cytoskeleton, and/or externally by the ECM via large multiprotein adhesions (focal adhesions). The actin filament network modulates mechanotransduction, and components of the protein translation machinery (e.g., eEF1A and eIF4E as well as mRNAs) associate with actin filaments. Localized protein synthesis allows for fast cell responses to internal and external forces. Abbreviations: AA = amino acid, mRNA = messenger ribonucleic acid, tRNA = transfer ribonucleic acid, TF = trigger factor, EF-G = elongation factor G, GTP = guanosine triphosphate, GDP = guanosine diphosphate, ECM = extracellular matrix, ER = endoplasmic reticulum, eIF2α = eukaryotic initiation factor 2α, eIF4E = eukaryotic initiation factor 4E, eEF1A = eukaryotic elongation factor 1A, GCN2 = general control nonderepressible 2, P = phosphorylation, aaRS = aminoacyl-tRNA synthetase.