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  current news   Press   selected story    
     
  22 July 2016  
 
Structural basis of suppression of host translation termination by Moloney Murine Leukemia Virus
 
 




Authors
Xuhua Tang1, Yiping Zhu2.3, Stacey L. Baker4, Matthew W. Bowler5,6, Benjamin Jieming Chen1, Chen Chen1, J. Robert Hogg4,#, Stephen P. Goff2,3,# and  Haiwei Song1,7,8,#

1   Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
2   Department of Biochemistry and Molecular Biophysics, Columbia University, HHSC 1310C, 701 W.     168th St., New York, NY 10032, USA
3   Howard Hughes Medical Institute, Columbia University, HHSC 1310C, 701 W. 168th St., New York, NY     10032, USA
4   Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of     Health, 50 South Drive, Bethesda, MD 20892, USA
5   European Molecular Biology Laboratory, Grenoble Outstation, 71 avenue des Martyrs,
    CS 90181 F-38042 Grenoble, France
6   Unit of Virus Host-Cell Interactions, Univ. Grenoble Alpes-EMBL-CNRS, 71 avenue des Martyrs, CS     90181 F-38042 Grenoble, France
7   Life Sciences Institute, Zhejiang University, 388 Yuhangtang Road, Hangzhou 310058, China
8   Department of Biochemistry, National University of Singapore, 14 Science Drive, Singapore 117543,     Singapore

#Correspondence should be addressed to S.P.G. (spg1@cumc.columbia.edu) or J.R.H. (j.hogg@nih.gov) or H.S. (haiwei@imcb.a-star.edu.sg)

Published in Nature Communications on 22 June 2016.

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 readthrough 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 readthrough 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 synthesis of its own proteins. 



Figure. 1. Overall structure of MoMLV-RT complex with mouse eRF1. 
Domains N, M, and C of eRF1 are colored in pink, lightblue and green, respectively. MoMLV RT polymerase domain is colored in grey and RNase H domain in yellow.


Figure. 2. Model for the mechanism of RT RNase H domain to promote readthough in cis.  The cartoon shows termination suppression activity may be strongest in cis, due to the newly synthesized MoMLV-RT RNase H polypeptide reaching back at the upstream termination codon on the same mRNA to interact with eRF1 and enhance readthrough.

For more information on Haiwei SONG's lab, please click here.