Non-cooperative 4E-BP2 folding with exchange between eIF4E-binding and binding-incompatible states tunes cap-dependent translation inhibition

Jennifer E. Dawson, Alaji Bah, Zhenfu Zhang, Robert M. Vernon, Hong Lin, P. Andrew Chong, Manasvi Vanama, Nahum Sonenberg, Claudiu C. Gradinaru and Julie D. Forman-Kay ()
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Jennifer E. Dawson: The Hospital for Sick Children
Alaji Bah: The Hospital for Sick Children
Zhenfu Zhang: University of Toronto
Robert M. Vernon: The Hospital for Sick Children
Hong Lin: The Hospital for Sick Children
P. Andrew Chong: The Hospital for Sick Children
Manasvi Vanama: The Hospital for Sick Children
Nahum Sonenberg: McGill University
Claudiu C. Gradinaru: University of Toronto
Julie D. Forman-Kay: The Hospital for Sick Children

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract Phosphorylation of intrinsically disordered eIF4E binding proteins (4E-BPs) regulates cap-dependent translation by weakening their ability to compete with eIF4G for eIF4E binding within the translation initiation complex. We previously showed that phosphorylation of T37 and T46 in 4E-BP2 induces folding of a four-stranded beta-fold domain, partially sequestering the canonical eIF4E-binding helix. The C-terminal intrinsically disordered region (C-IDR), remaining disordered after phosphorylation, contains the secondary eIF4E-binding site and three other phospho-sites, whose mechanisms in inhibiting binding are not understood. Here we report that the domain is non-cooperatively folded, with exchange between beta strands and helical conformations. C-IDR phosphorylation shifts the conformational equilibrium, controlling access to eIF4E binding sites. The hairpin turns formed by pT37/pT46 are remarkably stable and function as transplantable units for phospho-regulation of stability. These results demonstrate how non-cooperative folding and conformational exchange leads to graded inhibition of 4E-BP2:eIF4E binding, shifting 4E-BP2 into an eIF4E binding-incompatible conformation and regulating translation initiation.

Date: 2020
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DOI: 10.1038/s41467-020-16783-8

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