eIF2γ mutation that disrupts eIF2 complex integrity links intellectual disability to impaired translation initiation

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Item Type:	Article
Title:	eIF2γ mutation that disrupts eIF2 complex integrity links intellectual disability to impaired translation initiation
Creators Name:	Borck, G., Shin, B.S., Stiller, B., Mimouni-Bloch, A., Thiele, H., Kim, J.R., Thakur, M., Skinner, C., Aschenbach, L., Smirin-Yosef, P., Har-Zahav, A., Nürnberg, G., Altmüller, J., Frommolt, P., Hofmann, K., Konen, O., Nürnberg, P., Munnich, A., Schwartz, C.E., Gothelf, D., Colleaux, L., Dever, T.E., Kubisch, C. and Basel-Vanagaite, L.
Abstract:	Together with GTP and initiator methionyl-tRNA, translation initiation factor eIF2 forms a ternary complex that binds the 40S ribosome and then scans an mRNA to select the AUG start codon for protein synthesis. Here, we show that a human X-chromosomal neurological disorder characterized by intellectual disability and microcephaly is caused by a missense mutation in eIF2γ (encoded by EIF2S3), the core subunit of the heterotrimeric eIF2 complex. Biochemical studies of human cells overexpressing the eIF2γ mutant and of yeast eIF2γ with the analogous mutation revealed a defect in binding the eIF2β subunit to eIF2γ. Consistent with this loss of eIF2 integrity, the yeast eIF2γ mutation impaired translation start codon selection and eIF2 function in vivo in a manner that was suppressed by overexpressing eIF2β. These findings directly link intellectual disability to impaired translation initiation, and provide a mechanistic basis for the human disease due to partial loss of eIF2 function.
Keywords:	Amino Acid Sequence, Base Sequence, Eukaryotic Initiation Factor-2, Intellectual Disability, Molecular Models, Missense Mutation, Translational Peptide Chain Initiation, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Saccharomyces cerevisiae Proteins / Metabolism
Source:	Molecular Cell
ISSN:	1097-2765
Publisher:	Cell Press
Volume:	48
Number:	4
Page Range:	641-6
Date:	30 November 2012
Official Publication:	https://doi.org/10.1016/j.molcel.2012.09.005
PubMed:	View item in PubMed

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