Abstract
Retroviral reverse transcriptase (RT) of Moloney murine leukemia virus (MoMLV) is expressed in the form of a large Gag–Pol precursor protein by suppression of translational termination in which the maximal efficiency of stop codon read-through depends on the interaction between MoMLV RT and peptidyl release factor 1 (eRF1). Here, we report the crystal structure of MoMLV RT in complex with eRF1. The MoMLV RT interacts with the C-terminal domain of eRF1 via its RNase H domain to sterically occlude the binding of peptidyl release factor 3 (eRF3) to eRF1. Promotion of read-through by MoMLV RNase H prevents nonsense-mediated mRNA decay (NMD) of mRNAs. Comparison of our structure with that of HIV RT explains why HIV RT cannot interact with eRF1. Our results provide a mechanistic view of how MoMLV manipulates the host translation termination machinery for the synthesis of its own proteins.
Highlights
Retroviral reverse transcriptase (RT) of Moloney murine leukemia virus (MoMLV) is expressed in the form of a large Gag–Pol precursor protein by suppression of translational termination in which the maximal efficiency of stop codon read-through depends on the interaction between MoMLV RT and peptidyl release factor 1
We show that MoMLV RNase H promotes stop codon read-through, which in turn prevents nonsense-mediated messenger RNA (mRNA) decay (NMD)
MoMLV RT contains an N-terminal polymerase domain and C-terminal RNase H domain connected by a flexible linker, which is not visible in the electron density map and is assumed to be disordered
Summary
Retroviral reverse transcriptase (RT) of Moloney murine leukemia virus (MoMLV) is expressed in the form of a large Gag–Pol precursor protein by suppression of translational termination in which the maximal efficiency of stop codon read-through depends on the interaction between MoMLV RT and peptidyl release factor 1 (eRF1). We showed that MoMLV utilized its RT to interact with host eRF1, thereby promoting stop codon read-through to make Gag–Pol[19]. We show that MoMLV RNase H promotes stop codon read-through, which in turn prevents nonsense-mediated mRNA decay (NMD). These results reveal the structural basis of host translation termination suppression by MoMLV
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