期刊
MOLECULAR CELL
卷 48, 期 4, 页码 641-646出版社
CELL PRESS
DOI: 10.1016/j.molcel.2012.09.005
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资金
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- Israeli Ministry of Health Chief Scientist foundation [34963]
- Israeli Science Foundation [09/558]
- South Carolina Department of Disabilities and Special Needs
- Centre National de la Recherche Scientifique
- Fondation de France
Together with GTP and initiator methionyl-tRNA, translation initiation factor elF2 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 elF2 gamma (encoded by EIF2S3), the core subunit of the heterotrimeric elF2 complex. Biochemical studies of human cells overexpressing the elF2 gamma mutant and of yeast elF2 gamma with the analogous mutation revealed a defect in binding the elF2 beta subunit to elF2 gamma. Consistent with this loss of elF2 integrity, the yeast elF2 gamma mutation impaired translation start codon selection and elF2 function in vivo in a manner that was suppressed by overexpressing elF2 beta. These findings directly link intellectual disability to impaired translation initiation, and provide a mechanistic basis for the human disease due to partial loss of elF2 function.
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