GTP binding to translation factor eIF2B stimulates its guanine nucleotide exchange activity

Summary: 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...

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Autores principales:	Christopher J. Kershaw, Martin D. Jennings, Francesco Cortopassi, Margherita Guaita, Hawra Al-Ghafli, Graham D. Pavitt
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Biological sciences Molecular biology Cell biology Biomechanics Science Q
Acceso en línea:	https://doaj.org/article/63576347261d43b39ec105640f9c4851
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spelling	oai:doaj.org-article:63576347261d43b39ec105640f9c48512021-11-28T04:36:43ZGTP binding to translation factor eIF2B stimulates its guanine nucleotide exchange activity2589-004210.1016/j.isci.2021.103454https://doaj.org/article/63576347261d43b39ec105640f9c48512021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589004221014255https://doaj.org/toc/2589-0042Summary: 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 in vitro. 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.Christopher J. KershawMartin D. JenningsFrancesco CortopassiMargherita GuaitaHawra Al-GhafliGraham D. PavittElsevierarticleBiological sciencesMolecular biologyCell biologyBiomechanicsScienceQENiScience, Vol 24, Iss 12, Pp 103454- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biological sciences Molecular biology Cell biology Biomechanics Science Q
spellingShingle	Biological sciences Molecular biology Cell biology Biomechanics Science Q Christopher J. Kershaw Martin D. Jennings Francesco Cortopassi Margherita Guaita Hawra Al-Ghafli Graham D. Pavitt GTP binding to translation factor eIF2B stimulates its guanine nucleotide exchange activity
description	Summary: 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 in vitro. 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.
format	article
author	Christopher J. Kershaw Martin D. Jennings Francesco Cortopassi Margherita Guaita Hawra Al-Ghafli Graham D. Pavitt
author_facet	Christopher J. Kershaw Martin D. Jennings Francesco Cortopassi Margherita Guaita Hawra Al-Ghafli Graham D. Pavitt
author_sort	Christopher J. Kershaw
title	GTP binding to translation factor eIF2B stimulates its guanine nucleotide exchange activity
title_short	GTP binding to translation factor eIF2B stimulates its guanine nucleotide exchange activity
title_full	GTP binding to translation factor eIF2B stimulates its guanine nucleotide exchange activity
title_fullStr	GTP binding to translation factor eIF2B stimulates its guanine nucleotide exchange activity
title_full_unstemmed	GTP binding to translation factor eIF2B stimulates its guanine nucleotide exchange activity
title_sort	gtp binding to translation factor eif2b stimulates its guanine nucleotide exchange activity
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/63576347261d43b39ec105640f9c4851
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GTP binding to translation factor eIF2B stimulates its guanine nucleotide exchange activity

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