Published online 4 August 2004
Nucleic Acids Research, Vol. 32 No. 14 © Oxford University Press 2004; all rights reserved
A minimum structure of aminoglycosides that causes an initiation shift of trans-translation
1 Department of Biochemistry and Biotechnology, Faculty of Agriculture and Life Science and 2 Department of Biology, Faculty of Science, Hirosaki University, Hirosaki 036-8561, Japan
* To whom correspondence should be addressed. Tel: +81 172 39 3592; Fax: +81 172 39 3593; Email: himeno{at}cc.hirosaki-u.ac.jp
Received June 19, 2004; Revised July 11, 2004; Accepted July 20, 2004
Trans-translation is an unusual translation in which transfer-messenger RNA plays a dual function—as a tRNA and an mRNA—to relieve the stalled translation on the ribosome. It has been shown that paromomycin, a typical member of a 4,5-disubstituted class of aminoglycosides, causes a shift of the translation-resuming point on the tmRNA by –1 during trans-translation. To address the molecular basis of this novel effect, we examined the effects of various aminoglycosides that can bind around the A site of the small subunit of the ribosome on trans-translation in vitro. Tobramycin and gentamicin, belonging to the 4,6-disubstituted class of aminoglycosides having rings I and II similar to those in the 4,5-disubstituted class, possess similar effects. Neamine, which has only rings I and II, a common structure shared by 4,5- and 4,6-disubstituted classes of aminoglycosides, was sufficient to cause an initiation shift of trans-translation. In contrast, streptomycin or hygromycin B, lacking ring I, did not cause an initiation shift. The effect of each aminoglycoside on trans-translation coincides with that on conformational change in the A site of the small subunit of the ribosome revealed by recent structural studies: paromomycin, tobramycin and geneticin which is categorized into the gentamicin subclass, but not streptomycin and hygromycin B, flip out two conserved adenine bases at 1492 and 1493 from the A site helix. The pattern of initiation shifts by paromomycin fluctuates with variation of mutations introduced into a region upstream of the initiation point.
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