The Origin and Evolution of Release Factors: Implications for Translation Termination, Ribosome Rescue, and Quality Control Pathways

Abstract

The evolution of release factors catalyzing the hydrolysis of the final peptidyl-tRNA bond and the release of the polypeptide from the ribosome has been a longstanding paradox. While the components of the translation apparatus are generally well-conserved across extant life, structurally unrelated release factor peptidyl hydrolases (RF-PHs) emerged in the stems of the bacterial and archaeo-eukaryotic lineages. We analyze the diversification of RF-PH domains within the broader evolutionary framework of the translation apparatus. Thus, we reconstruct the possible state of translation termination in the Last Universal Common Ancestor with possible tRNA-like terminators. Further, evolutionary trajectories of the several auxiliary release factors in ribosome quality control (RQC) and rescue pathways point to multiple independent solutions to this problem and frequent transfers between superkingdoms including the recently characterized ArfT, which is more widely distributed across life than previously appreciated. The eukaryotic RQC system was pieced together from components with disparate provenance, which include the long-sought-after Vms1/ANKZF1 RF-PH of bacterial origin. We also uncover an under-appreciated evolutionary driver of innovation in rescue pathways: effectors deployed in biological conflicts that target the ribosome. At least three rescue pathways (centered on the prfH/RFH, baeRF-1, and C12orf65 RF-PH domains), were likely innovated in response to such conflicts.

Evolution of the standard genetic code

“…Moreover, termination factors are sophisticated protein catalysts (e.g., Adio et al 2018) that cannot exist until translation itself is sophisticated. Such considerations suggest that translation termination also took its final form late, after separation of life's domains (Burroughs and Aravind 2019). Thus the suggestion of a majority of quickly encoded functions (≈ 20) and a small number added later by a different logic (≈ 2) has extensive, long-standing molecular support.…”

Carboxylic Ester Hydrolases in Bacteria: Active Site, Structure, Function and Application

“…A common feature of RF-1 family peptidyl-tRNA hydrolase is a GGQ motif. Gln in this motif works as a base that stabilizes nucleophilic water, and also plays a key role in interactions with tRNA [204]. The O ε 1 of Gln28 in YaeJ, a peptidyl-tRNA hydrolase from E. coli (PDB code: 4V95) and the nucleophilic water molecule, form a hydrogen bond [134].…”

Chaos, Order and Systematics in Evolution of the Genetic Code

“…To encode tryptophan, the anticodon CCA is used. The UCA anticodon, however, is not generally utilized because UCA corresponds to the UGA stop codon, which is recognized in mRNA by a protein release factor [79]. To encode methionine, anticodon CAU is utilized to read AUG codons.…”

“…Some of the last amino acids to enter the code occupy disfavored 3 rd position A (Phe, Tyr, Cys, Trp). Stop codons, which are read in mRNA by protein release factors [79], occupy disfavored row 1 (3 rd position A).…”

“…Stop codons are recognized by protein release factors as codons in mRNA, with no corresponding anticodon in tRNA, consistent with A being disfavored in the anticodon 3 rd position. Protein release factors recognize stop codons to release the nascent peptide from the ribosome [79]. So, C is favored in the anticodon, in the 2 nd and 3 rd anticodon positions.…”