This study combines molecular dynamics simulations and discrete path sampling to construct energy landscapes for a doubly phosphorylated 4E-BP218-62. These results explain some interesting experimental observations including the low stability of doubly phosphorylated 4E-BP2 and its moderate binding to eIF4E and the inability of phosphorylated Y54A/L59A to fold.
Study demonstrated key roles for 4E-BP1 and 4E-BP2 during tumor development and during tumor hypoxia. These factors maintain an ability to slow tumor progression in prostate cancer in the face of constitutive mTOR activation arising from loss of PTEN and are also important in promoting survival of hypoxic cells once cancer has developed
Results suggest that IGF2BP3 promotes eIF4E-mediated translational activation through the reduction of EIF4E-BP2 via mRNA degradation leading to enhanced cell proliferation.
results highlight stabilization of a phosphorylation-induced fold as the essential mechanism for phospho-regulation of the 4E-BP:eIF4E interaction and exemplify a new mode of biological regulation mediated by intrinsically disordered proteins
mTORC1 controls mitochondrial activity and biogenesis by selectively promoting translation of nucleus-encoded mitochondria-related mRNAs via inhibition of the eukaryotic translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs).
Data show that the eIF4E binding preference for 4E-BP2 over 4E-BP1 is based on stacking of Arg63 side chain on Trp73 indole ring of eIF4E and construction of hydrophobic space around the Trp73 indole ring by the Leu59-Leu60 sequence of 4E-BP2.
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