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.

Ribosome exit tunnel electrostatics

“…The axial electrical field resulting from the combination of the cylindrical geometry for 75% of the tunnel length (0.75 L) from its entry point and of the truncated cone geometry for the remaining 25% (0.25 L) of the length in the ribosome exit tunnel, with or without an added Lorentzian peak (see below), is the superposition of equations (22) and (41). The parameter settings have to be consistent with the chosen geometry and with the surface charge densities (σ 1 and σ 2 ).…”

“…Reading in the given input peptide sequence Step c) Compute the ordered list of axial electric fields for each of the previous axial positions using formula (22) for the idealized cylindrical model, formula (49) or formula (55) for the realistic model, incorporating the Lorentzian peak and the truncated cone geometry at the end side of the tunnel, respectively. It should be emphasized that due to the symmetry of the potential barrier in the idealized cylindrical model and its finite length, a clustered local enrichment in positive (negative) charge in a polypeptide sequence will first be attracted (repelled) when entering into the tunnel and will then be pulled inside (pushed outside) the tunnel when emerging at the tunnel exit point.…”

“…Although the average codon translation rate is rather constant transcriptome wide, estimated at 5.6 amino acid residues per second in eukaryotes, codon translation rates have been shown to vary up to 100-fold across a single transcript [8,9]. Many factors influence translation speeds across a single transcript (mRNA), including differences in cognate, near-cognate and non-cognate tRNA relative abundance, nascentchain charged residues inside the ribosome exit tunnel, mRNA secondary structure, proline residues at either A or P site of the ribosome, steric hindrance between contiguous ribosomes translating the same mRNA molecule, and the finite resource of the ribosome pool available in the cell [10][11][12][13][14][15][16][17][18][19][20][21][22]. The individual contributions of each of the previous factors to the rate of the translation are difficult to assess quantitatively and separately.…”

“…codon ordering allowing tRNA recycling (reusage of the same tRNA at successive encodings of the same amino acid can speed up translation or favor fidelity[44,45]). The elongation speed may also independently be impeded by downstream mRNA secondary structures[21,22,33,34].The eukaryote ribosome exit tunnel can accommodate at least 40 amino acid residues and up to more than 70. It is known that the nascent polypeptide can start folding, i.e.…”

Manipulation of Axonal Outgrowth via Exogenous Low Forces

“…The cytoskeleton, in addition to providing structural support, is also mainly responsible for modulating activity and localizing the proteins, organelles and vesicles [111]. Low mechanical forces have an effect on the actin cytoskeleton [112] and on MT dynamics [78].…”