GTP Binding to Translation Factor EIF2B Stimulates Its Guanine Nucleotide Exchange Activity

Overview

Journal iScience

Publisher Cell Press

Date 2021 Dec 8

PMID 34877508

Citations 5

Authors

Christopher J Kershaw

Martin D Jennings

Francesco Cortopassi

Margherita Guaita

Hawra Al-Ghafli

Graham D Pavitt

Affiliations

Soon will be listed here.

Abstract

eIF2B is the guanine nucleotide exchange factor (GEF) required for cytoplasmic protein synthesis initiation in eukaryotes and its regulation within the integrated stress response (ISR). It activates its partner factor eIF2, thereby promoting translation initiation. Here we provide evidence through biochemical and genetic approaches that eIF2B can bind directly to GTP and this can enhance its rate of GEF activity toward eIF2-GDP . GTP binds to a subcomplex of the eIF2Bγ and ε subunits. The eIF2Bγ amino-terminal domain shares structural homology with hexose sugar phosphate pyrophosphorylase enzymes that bind specific nucleotides. A K66R mutation in eIF2Bγ is especially sensitive to guanine or GTP in a range of functional assays. Taken together, our data suggest eIF2Bγ may act as a sensor of purine nucleotide availability and thus modulate eIF2B activity and protein synthesis in response to fluctuations in cellular nucleotide levels.

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