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2014 ; 512
(7514
): 328-32
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Dynamic pathways of -1 translational frameshifting
#MMPMID24919156
Chen J
; Petrov A
; Johansson M
; Tsai A
; O'Leary SE
; Puglisi JD
Nature
2014[Aug]; 512
(7514
): 328-32
PMID24919156
show ga
Spontaneous changes in the reading frame of translation are rare (frequency of
10(-3) to 10(-4) per codon), but can be induced by specific features in the
messenger RNA (mRNA). In the presence of mRNA secondary structures, a
heptanucleotide 'slippery sequence' usually defined by the motif X XXY YYZ, and
(in some prokaryotic cases) mRNA sequences that base pair with the 3' end of the
16S ribosomal rRNA (internal Shine-Dalgarno sequences), there is an increased
probability that a specific programmed change of frame occurs, wherein the
ribosome shifts one nucleotide backwards into an overlapping reading frame (-1
frame) and continues by translating a new sequence of amino acids. Despite
extensive biochemical and genetic studies, there is no clear mechanistic
description for frameshifting. Here we apply single-molecule fluorescence to
track the compositional and conformational dynamics of individual ribosomes at
each codon during translation of a frameshift-inducing mRNA from the dnaX gene in
Escherichia coli. Ribosomes that frameshift into the -1 frame are characterized
by a tenfold longer pause in elongation compared to non-frameshifted ribosomes,
which translate through unperturbed. During the pause, interactions of the
ribosome with the mRNA stimulatory elements uncouple EF-G catalysed translocation
from normal ribosomal subunit reverse-rotation, leaving the ribosome in a
non-canonical intersubunit rotated state with an exposed codon in the
aminoacyl-tRNA site (A site). tRNA(Lys) sampling and accommodation to the empty A
site and EF-G action either leads to the slippage of the tRNAs into the -1 frame
or maintains the ribosome into the 0 frame. Our results provide a general
mechanistic and conformational framework for -1 frameshifting, highlighting
multiple kinetic branchpoints during elongation.
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