Cotranslational Folding of Proteins on the Ribosome - PubMed (original) (raw)

Review

Cotranslational Folding of Proteins on the Ribosome

Marija Liutkute et al. Biomolecules. 2020.

Abstract

Many proteins in the cell fold cotranslationally within the restricted space of the polypeptide exit tunnel or at the surface of the ribosome. A growing body of evidence suggests that the ribosome can alter the folding trajectory in many different ways. In this review, we summarize the recent examples of how translation affects folding of single-domain, multiple-domain and oligomeric proteins. The vectorial nature of translation, the spatial constraints of the exit tunnel, and the electrostatic properties of the ribosome-nascent peptide complex define the onset of early folding events. The ribosome can facilitate protein compaction, induce the formation of intermediates that are not observed in solution, or delay the onset of folding. Examples of single-domain proteins suggest that early compaction events can define the folding pathway for some types of domain structures. Folding of multi-domain proteins proceeds in a domain-wise fashion, with each domain having its role in stabilizing or destabilizing neighboring domains. Finally, the assembly of protein complexes can also begin cotranslationally. In all these cases, the ribosome helps the nascent protein to attain a native fold and avoid the kinetic traps of misfolding.

Keywords: cotranslational protein folding; nascent polypeptides; polypeptide exit tunnel; protein synthesis; ribosome; translation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Schematic of cotranslational protein folding. Folding begins early inside the polypeptide exit tunnel. The nascent chain (NC) emerging from the ribosome can interact with chaperones, biogenesis factors, or other proteins. Small and large ribosomal subunits are shown in light and dark gray, respectively; the tRNA (green) with the nascent peptide (magenta) is shown as the ribosome moves along the mRNA (red) and the growing nascent chain moves through the polypeptide exit tunnel (light yellow). Protein partners interacting with the nascent peptide are depicted in blue.

Figure 2

Dimensions of the peptide exit tunnel in ribosomes from prokaryotic and eukaryotic origin [34,38]. Color visualizes the electrostatic potential within the tunnel.

Figure 3

Examples of structures of nascent peptides in the polypeptide exit tunnel. Nascent peptides can interact with the tunnel walls as shown for TnaC [68], MifM [69], SecM [70], and CMV [71], or form α-helices in the upper and lower regions of the tunnel, as illustrated for VemP [62] and DNA topoisomerase peptides [61]. An α-helical structure of dipeptidylaminopeptidase B (DPAP-B) and the AAP peptide in the tunnel are also shown [60,71]. Structures shown on gray background are visualized using the PDB coordinates (PDB ID left to right: 4UY8; 3J9W; 3JBU; 5NWY; 5NP6). The coordinates of structures shown on white background are not available as PDB entries and are reproduced from the respective journals, with permission.

Figure 4

Tertiary structures of nascent peptides on the ribosome (adapted with permissions). (a) Cryo-electron microscopy (cryoEM) structure of the Zn-finger domain of ARD1 deep inside the exit tunnel of the ribosome. Figure adapted from [51]. (b) Cryo-EM structure of partially folded states of the spectrin domain at the exit tunnel vestibule, adapted from [16]. Root-mean-square deviation (RMSD) indicates the deviation of the native spectrin domain structure (PDB: 1AJ3) from the cryo-EM density map (EMD-3451) of the domain conformation at the ribosome surface. (c) Nuclear magnetic resonance (NMR) structures of the disordered FLN6 domain (cyan) and natively folded FLN5 (magenta), with representative conformations of FLN5 on the ribosome; figure adapted from [82]. (d) NMR structures of the native state (left) and an ensemble of intermediate states (right) for FLN5 on the ribosome [78].

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Cotranslational Folding of Proteins on the Ribosome - PubMed (original) (raw)