Structural characterization of the Z RING-eIF4E complex reveals a distinct mode of control for eIF4E.
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.
Volpon
Laurent
L
Institute of Research in Immunology and Cancer, Department of Pathology and Cell Biology, Université de Montréal, Pavillion Marcelle-Coutu, Chemin Polytechnique, Montreal, QC, Canada.
Osborne
Michael J
MJ
Capul
Althea A
AA
de la Torre
Juan C
JC
Borden
Katherine L B
KL
D000595:Amino Acid Sequence; D018049:Arenaviruses, Old World / Q000737:chemistry; D001665:Binding Sites / Q000235:genetics; D055592:Biophysical Phenomena; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D039561:Eukaryotic Initiation Factor-4E / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D039603:Eukaryotic Initiation Factor-4G / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008958:Models, Molecular; D046912:Multiprotein Complexes; D019906:Nuclear Magnetic Resonance, Biomolecular; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D016335:Zinc Fingers
D002352:Carrier Proteins; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D046912:Multiprotein Complexes; C117526:p11 Z protein, Lymphocytic choriomeningitis virus