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  current news   Press   selected story    
     
  28 November 2012  
  Structural Basis of the PNRC2-Mediated Link between mRNA Surveillance and Decapping
 
 



Authors
Tingfeng Lai1,2,9, Hana Cho3,9, Zhou Liu4, Matthew W Bowler5,6, Shunfu Piao1, Roy Parker7, Yoon Ki Kim3 and  Haiwei Song1,4,8.

1- Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673.
2- School of Biological Sciences, Nanyang Technological University, 50 Nanyang Avenue, Singapore     639798.
3- School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
4- Life Sciences Institute, Zhejiang University, 388 Yuhangtang Road, Hangzhou, China.
5- European Molecular Biology Laboratory, 6 rue Jules Horowitz, BP 181, 38042, Grenoble, France.
6- Unit of Virus Host-Cell Interactions, UJF-EMBL-CNRS, UMI 3265, 6 rue Jules Horowitz, 38042 Grenoble     Cedex 9, France.  
7- Department of Molecular and Cellular Biology and Howard Hughes Medical Institute, University of     Arizona, Tucson, AZ 85721, USA.
8- Department of Biochemistry, National University of Singapore, 14 Science Drive, Singapore 117543.
9- These two authors contribute equally to this work

Published in Structure on Oct 18, 2012.

Abstract

Nonsense-mediated mRNA decay (NMD) is an important mRNA surveillance system and human PNRC2 protein mediates the link between mRNA surveillance and decapping.  However, the mechanism by which PNRC2 interacts with the mRNA surveillance machinery and stimulates NMD is unknown.  Here we present the crystal structure of Dcp1a in complex with PNRC2. The proline-rich region of PNRC2 is bound to the EVH1 domain of Dcp1a while its NR-box mediates the interaction with the hyperphosphorylated Upf1. The mode of PNRC2 interaction with Dcp1a is distinct from those observed in other EVH1/proline-rich ligands interactions. Disruption of the interaction of PNRC2 with Dcp1a abolishes its P-body localization and ability to promote mRNA degradation when tethered to mRNAs. PNRC2 acts in synergy with Dcp1a to stimulate the decapping activity of Dcp2 by bridging the interaction between Dcp1a and Dcp2, suggesting that PNRC2 is a decapping coactivator in addition to its adaptor role in NMD.

Figure Legend: Comparison of Dcp1aEVH1 with EVH1 domains from ScDcp1, Mena, Homer and N-Wasp. (A) Schematic diagrams of domain organization of PNRC2 and hDcp1a. SH3-binding motif, PRS region and the NR box of PNRC2 are colored in red, pink and cyan respectively while the EVH1 and the trimerization domains are shown in pale green and yellow. (B) Structure of Dcp1aEVH1 (pale green) in complex with PNRC2 (pink) with secondary elements labeled and the N-terminal helix colored in blue. (C) Structure of ScDcp1 (pale green) with the N-terminal region and the insertion helices shown in blue and orange, respectively. (D) Structure of Mena EVH1 domain (lemon) in complex with the FPPPP peptide from ActA (magenta). (E) Structure of the Homer EVH1 domain (lemon) in complex with TPPSPF peptide from mGluR (magenta). (F) NMR structure of N-Wasp EVH1 (lemon) in complex with WIP peptide (magenta).



For more information on Haiwei SONG’s laboratory, please click here.