Mechanochemistry in Translation

Abstract

As the influence of translation rates on protein folding and function has come to light, the mechanisms by which translation speed is modulated have become an important issue. One mechanism entails the generation of force by the nascent protein. Cotranslational processes, such as nascent protein folding, the emergence of unfolded nascent chain segments from the ribosome’s exit tunnel, and insertion of the nascent chain into or translocation of the nascent chain through membranes, can generate forces that are transmitted back to the peptidyl transferase center and affect translation rates. In this Perspective, we examine the processes that generate these forces, the mechanisms of transmission along the ribosomal exit tunnel to the peptidyl transferase center, and the effects of force on the ribosome’s catalytic cycle. We also discuss the physical models that have been developed to predict and explain force generation for individual processes and speculate about other processes that may generate forces that have yet to be tested.

Residue-by-residue analysis of cotranslational membrane protein integration in vivo

“…In contrast, in constructs where little force is exerted on the AP, pausing will be efficient and more of the arrested form of the protein will be produced ( Figure 1b , left and right). The fraction full-length protein produced, f FL = I FL /( I FL +I A ), where I FL and I A are the intensities of the bands representing the full-length ( FL ) and arrested ( A ) species on an SDS-PAGE gel ( Figure 1c and Figure 1—figure supplement 1 ), can therefore be used as a proxy for F in a given construct ( Kemp et al, 2020 ; Niesen et al, 2018 ; Leininger et al, 2019 ). A plot of f FL versus N – a force profile (FP) – thus can provide a detailed picture of the cotranslational process in question, as reflected in the variation in the force exerted on the nascent chain during translation.…”

Cotranslational folding stimulates programmed ribosomal frameshifting in the alphavirus structural polyprotein

“…12 It should be noted that the implications of these findings potentially extend beyond the realm of viral proteins. A wide variety of molecular transitions have been found to generate tension within the nascent chain including the folding of soluble domains near the ribosomal exit tunnel 43,48 and the translocon-mediated membrane integration of nascent TM domains. 40,41 These observations suggest the tension in the nascent chain should fluctuate as the structural features emerge from the ribosome (Fig.…”

“…This translational feedback constitutes a new form of mechanochemical allostery on the ribosome. 48 Additional investigations are needed to explore the potential relevance of this type of cotranslational feedback to protein homeostasis. Indeed, interactions between the nascent chain and molecular chaperones are known to ratchet polypeptides across the membrane, 49,50 and may therefore contribute to pulling forces.…”

Force transduction creates long-ranged coupling in ribosomes stalled by arrest peptides

“…This is contrasted with intra-chain interactions such as in alpha helices which can move as a unit and therefore do not inhibit the propagation of force and allow breaking of interactions in non-consecutive order. The force-induced restarting pathways of SecM and VemP both highlight the need to consider potential interactions between the nascent chain and the ribosome when estimating the co-translational forces experienced by the ribosome [33,34]. Fortunately, characterization and understanding of interactions between a nascent peptide and the exit tunnel are becoming increasingly available thanks to the rapid expansion of cryo-EM structural data.…”

“…Fortunately, characterization and understanding of interactions between a nascent peptide and the exit tunnel are becoming increasingly available thanks to the rapid expansion of cryo-EM structural data. Future simulations will provide an essential connection between the study of nascent chain behavior in the exit tunnel [35,36,37] and the role of forces in influencing cotranslational behavior [34,21].…”