Stepwise assembly of the eukaryotic translation initiation factor 2 complex

Abstract

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Binding of human Cdc123 to eIF2γ

“…Using yeast cell viability experiments, western blot analysis and two-hybrid assays, we show that ATP is important for the function of Hs-Cdc123 in eIF2 assembly. These data and recent findings (Chen et al, 2023;Vanselow et al, 2022) allow us to propose a refined model to explain the mechanism of action of Cdc123 in eIF2 assembly.…”

“…The crystallographic structure of Schizosaccharomyces pombe Cdc123 (Sp-Cdc123) showed that the protein belongs to the ATP grasp family. Binding of ATP was indeed observed in the structure and Cdc123 variants in the ATP binding pocket suggested that ATP was important for the Cdc123 function (Chen et al, 2023;Panvert et al, 2015;Perzlmaier et al, 2013;Vanselow et al, 2022). On the other hand, the crystallographic structure of Sp-Cdc123 bound to the domain 3 of eIF2g from Saccharomyces cerevisiae (Sc-eIF2gD3 or simply Sc-gD3) was determined (Sp-Cdc123:Sc-eIF2gD3).…”

“…In eukaryotes, the assembly of the heterotrimeric protein eIF2 is facilitated by the Cdc123 protein (Perzlmaier et al, 2013). Indeed, Cdc123 interacts with eIF2g (Bieganowski et al, 2004;Chen et al, 2023;Ho et al, 2002) and the association of eIF2g to eIF2a and eIF2b was shown to depend on the interaction of the C-terminal domain (D3) of eIF2g with Cdc123 in yeast and human (Panvert et al, 2015;Perzlmaier et al, 2013;Vanselow et al, 2022). Moreover, the C-terminal region of S. cerevisiae Cdc123 (the last 30 residues) is indispensable for its in vivo function (Panvert et al, 2015).…”

“…Moreover, the C-terminal region of S. cerevisiae Cdc123 (the last 30 residues) is indispensable for its in vivo function (Panvert et al, 2015). In yeast, human and plants, mutations in Cdc123 lower the availability of functional eIF2 and dysregulate protein synthesis triggering ISR (Chen et al, 2023;Perzlmaier et al, 2013;Vanselow et al, 2022;Young-Baird et al, 2020). Notably, mutations related to MEHMO syndrome (Mental deficiency, Epilepsy, Hypogenitalism, Microcephaly and Obesity), an X-linked intellectual disability, were found in the gene encoding eIF2g in mammals (EIF2S3) (Gregory et al, 2019;Kotzaeridou et al, 2020;Moortgat et al, 2016;Skopkova et al, 2017).…”

The Integrated Stress Response Is Tumorigenic and Constitutes a Therapeutic Liability in Somatotroph Adenomas

“…Integrated genomic data in breast cancer has shown that eIF2β is highly amplified and correlates to the aggressive behavior of luminal breast tumors [ 15 ]. eIF2γ has a catalytic site for GTPase activity and is involved in binding of the ternary complex to mRNA; the eIF2γ variant is associated with hypothalamo-pituitary development, hypopituitarism, and pancreatic dysfunction and glucose regulation [ 16 ]. The ISR is a double-edged sword with both pro-survival and pro-death activities, and regulation of ISR signaling components is a promising strategy in cancer therapy [ 17 , 18 ].…”