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Structural characterization of the Z ring-eIF4E complex reveals a distinct mode of control for eIF4E

Academic Article
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Overview

authors

  • Volpon, L.
  • Osborne, M. J.
  • Capul, A. A.
  • de la Torre, Juan
  • Borden, K. L. B.

publication date

  • March 2010

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • The eukaryotic translation initiation factor eIF4E, a potent oncogene, is highly regulated. One class of eIF4E regulators, including eIF4G and the 4E-binding proteins (4E-BPs), interact with eIF4E using a conserved YXXXXLPhi-binding site. The structural basis of this interaction and its regulation are well established. Really Interesting New Gene (RING) domain containing proteins, such as the promyelocytic leukemia protein PML and the arenaviral protein Z, represent a second class of eIF4E regulators that inhibit eIF4E function by decreasing eIF4E's affinity for its m(7)G cap ligand. To elucidate the structural basis of this inhibition, we determined the structure of Z and studied the Z-eIF4E complex using NMR methods. We show that Z interacts with eIF4E via a novel binding site, which has no homology with that of eIF4G or the 4E-BPs, and is different from the RING recognition site used in the ubiquitin system. Z and eIF4G interact with distinct parts of eIF4E and differentially alter the conformation of the m(7)G cap-binding site. Our results provide a molecular basis for how PML and Z RINGs reduce the affinity of eIF4E for the m(7)G cap and thereby act as key inhibitors of eIF4E function. Furthermore, our findings provide unique insights into RING protein interactions.

subject areas

  • Amino Acid Sequence
  • Arenaviruses, Old World
  • Binding Sites
  • Biophysical Phenomena
  • Carrier Proteins
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factor-4G
  • Ligands
  • Models, Molecular
  • Multiprotein Complexes
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Interaction Mapping
  • Protein Structure, Tertiary
  • Zinc Fingers
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Research

keywords

  • Lassa Fever Virus-Z
  • NMR
  • promyelocytic leukemia protein
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Identity

PubMed Central ID

  • PMC2851782

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0909877107

PubMed ID

  • 20212144
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Additional Document Info

start page

  • 5441

end page

  • 5446

volume

  • 107

issue

  • 12

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