Abstract
Within the larger ABC superfamily of ATPases, ABCF family members eEF3 in Saccharomyces cerevisiae and EttA in Escherichia coli have been found to function as ribosomal translation factors. Several other ABCFs including biochemically characterized VgaA, LsaA and MsrE confer resistance to antibiotics that target the peptidyl transferase center and exit tunnel of the ribosome. However, the diversity of ABCF subfamilies, the relationships among subfamilies and the evolution of antibiotic resistance (ARE) factors from other ABCFs have not been explored. To address this, we analyzed the presence of ABCFs and their domain architectures in 4505 genomes across the tree of life. We find 45 distinct subfamilies of ABCFs that are widespread across bacterial and eukaryotic phyla, suggesting that they were present in the last common ancestor of both. Surprisingly, currently known ARE ABCFs are not confined to a distinct lineage of the ABCF family tree, suggesting that ARE can readily evolve from other ABCF functions. Our data suggest that there are a number of previously unidentified ARE ABCFs in antibiotic producers and important human pathogens. We also find that ATPase-deficient mutants of all four E. coli ABCFs (EttA, YbiT, YheS and Uup) inhibit protein synthesis, indicative of their ribosomal function, and demonstrate a genetic interaction of ABCFs Uup and YheS with translational GTPase BipA involved in assembly of the 50S ribosome subunit. Finally, we show that the ribosome-binding resistance factor VmlR from Bacillus subtilis is localized to the cytoplasm, ruling out a role in antibiotic efflux.
Highlights
Protein biosynthesis – translation – is the reading and deciphering of information coded in genes to produce proteins
ABCFs are stepping into the limelight as important translation, ribosome assembly and antibiotic resistance factors
We have found hydrolysis-incompetent EQ2 mutants of all four E. coli ABCFs inhibit protein synthesis, suggesting they all function on the ribosome
Summary
Protein biosynthesis – translation – is the reading and deciphering of information coded in genes to produce proteins It is one of the most ancient and central cellular processes, and control of the various stages of translation is achieved via an intricate interplay of multiple molecular interactions. The ABC protein eEF3 (eukaryotic Elongation Factor 3) is an essential factor for polypeptide elongation in Saccharomyces cerevisiae [1] with proposed roles in E-site tRNA release and ribosome recycling [2,3,4] This fungi-specific translational ABC ATPase appeared to be an exception to the tenet that trGTPases are the enzymatic rulers of the ribosome, until ABCE1 ( known as Rli1), a highly conserved protein in eukaryotes and archaea, was identified as another ribosome recycling factor [5,6,7]
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