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A novel function of the MA-3 domains in transformation and translation suppressor Pdcd4 is essential for its binding to eukaryotic translation initiation factor 4A

  1. Author:
    Yang, H. S.
    Cho, M. H.
    Zakowicz, H.
    Hegamyer, G.
    Sonenberg, N.
    Colburn, N. H.

  2. Author Address

    Yang, HS, NCI, Canc Res Ctr, Gene Regulat Sect, Bldg 567,Rm 180, Frederick, MD 21702 USA NCI, Canc Res Ctr, Gene Regulat Sect, Frederick, MD 21702 USA. Seoul Natl Univ, Coll Vet Med & Agr Biotechnol, Toxicol Lab, Seoul 151742, South Korea. George Washington Univ, Genet Program, Washington, DC 20037 USA. McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada. McGill Univ, Canc Res Ctr, Montreal, PQ H3G 1Y6, Canada.
    1. Year: 2004
  2. Journal: Molecular and Cellular Biology
    1. 24
    2. 9
    3. Pages: 3894-3906
  4. Type of Article: Article
  1. Abstract:

    An alpha-helical MA-3 domain appears in several translation initiation factors, including human eukaryotic translation initiation factor 4G (eIF4G) and DAP-5/NAT1/p97, as well as in the tumor suppressor Pdcd4. The function of the MA-3 domain is, however, unknown. C-terminal eIF4G (eIG4Gc) contains an MA-3 domain that is located within the eIF4A-binding region, suggesting a role for eIF4A binding. Interestingly, C-terminal DAP-5/NAT1/p97 contains an MA-3 domain, but it does not bind to eIF4A. Mutation of amino acid residues conserved between Pdcd4 and eIF4Gc but not in DAP-5/NAT1/p97 to the amino acid residues found in the DAP-5/NAT1/p97 indicates that some of these amino acid residues within the MA-3 domain are critical for eIF4A-binding activity. Six Pdcd4 mutants (Pdcd4(E249K), Pdcd4(D253A), Pdcd4(D414K), Pdcd4(D418A), Pdcd4(E249K,D414K), and Pdcd4(D253A,D418A)) lost >90% eIF4A-binding activity. Mutation of the corresponding amino acid residues in the eIF4Gc also produced similar results, as seen for Pdcd4. These results demonstrate that the MA-3 domain is important for eIF4A binding and explain the ability of Pdcd4 or eIF4Gc but not DAP-5/NAT1/p97 to bind to eIF4A. Competition experiments indicate that Pdcd4 prevents ca. 60 to 70% of eIF4A binding to eIF4Gc at a Pdcd4/eIF4A ratio of 1:1, but mutants Pdcd4(D253A) and Pdcd4(D253A,D418A) do not. Translation of stem-loop structured mRNA is susceptible to inhibition by wild-type Pdcd4 but not by Pdcd4(D253A), Pdcd4(D418A), or Pdcd4(D235A,D418A). Together, these results indicate that not only binding to eIF4A but also prevention of eIF4A binding to the MA-3 domain of eIF4Gc contributes to the mechanism by which Pdcd4 inhibits translation

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