A C-term truncated EIF2Bγ protein encoded by an intronically polyadenylated isoform introduces unfavorable EIF2Bγ–EIF2γ interactions

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2022-10

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ODTÜ, Deniz Bilimleri Enstitüsü

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Eukaryotic translation initiates upon EIF2-GTP·Met-tRNAi ternary complex (TC) recruitment to the ribosomes. EIF2(α-γsubunits)is a GTPase. Within the EIF2 complex, EIF2γcarries the GTP. FollowingTC formation, EIF2-GDPis released from the ribosome.EIF2B (α-ε subunits)acts as a guanine exchange factor (GEF) andregulatesthe GDP to GTP exchange. In the EIF2B complex, EIF2Bε has a catalytic GEF domain. During stress-induced conditions, phosphorylation ofEIF2α turns EIF2into an inhibitor of EIF2Bforming an inactive EIF2:EIF2B complex. Withinthe inactive complex, EIF2γinteracts with EIF2Bγrather than EIF2Bε. In turn, inactive complex lacks GEF activity, therefore, decreases TC formation and triggers the internal stress response (ISR), which determines the cell fate. Deregulated ISR has been linked to neurodegenerative disorders and cancer.In this work, ourexperimental collaborators characterizedanupregulation ofan intronically polyadenylatedtranscript of EIF2Bγin breast cancer cells. Based on this finding, we examinedthe structural impactofthis isoformon EIF2-EIF2Binteraction. To that end, we generated structural models of EIF2Bγisoformsbound to theirinteracting partner EIF2γ. We alsoperformed residue-based interaction analysesin the presence of full-length and truncatedEIF2Bγ. Moreover, we dissected the electrostaticpotential maps of EIF2γ:EIF2Bγcomplexes. As a result, truncated isoformleadstounfavorable electrostaticinteractionsacross the EIF2γ:EIF2Bγinterface (where EIF2γ-K400and EIF2Bγ-R412 face each other)(Fig 1A). This observation is furtherconfirmed by our electrostatics maps analyses(Fig 1B-C). Based on this, we predict that the truncated EIF2Bγ isoform leadsto a potential decrease in the stability of the inactiveEIF2:EIF2B complex, which could explain its upregulation in the breast cancer cells.Our work got recently publishedin Proteins(Circiret al., Proteins, 2021) together with our models located at https://github.com/CSB-KaracaLab/eif2g-eif2bg-ints.

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https://hibit2022.ims.metu.edu.tr/
https://hdl.handle.net/11511/101321

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The International Symposium on Health Informatics and Bioinformatics

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Graduate School of Informatics, Conference / Seminar

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Citation Formats

D. B. E. ODTÜ, “A C-term truncated EIF2Bγ protein encoded by an intronically polyadenylated isoform introduces unfavorable EIF2Bγ–EIF2γ interactions,” Erdemli, Mersin, TÜRKİYE, 2022, p. 2095, Accessed: 00, 2023. [Online]. Available: https://hibit2022.ims.metu.edu.tr/.