Borck, Guntram, Shin, Byung-Sik, Stiller, Barbara, Mimouni-Bloch, Aviva, Thiele, Holger, Kim, Joo-Ran, Thakur, Meghna, Skinner, Cindy, Aschenbach, Lara, Smirin-Yosef, Pola, Har-Zahav, Adi, Nuernberg, Gudrun, Altmueller, Janine, Frommolt, Peter ORCID: 0000-0002-1966-8014, Hofmann, Kay, Konen, Osnat, Nuernberg, Peter, Munnich, Arnold, Schwartz, Charles E., Gothelf, Doron, Colleaux, Laurence, Dever, Thomas E., Kubisch, Christian ORCID: 0000-0003-4220-0978 and Basel-Vanagaite, Lina (2012). elF2 gamma Mutation that Disrupts elF2 Complex Integrity Links Intellectual Disability to Impaired Translation Initiation. Mol. Cell, 48 (4). S. 641 - 647. CAMBRIDGE: CELL PRESS. ISSN 1097-2765

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Borck, GuntramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shin, Byung-SikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stiller, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mimouni-Bloch, AvivaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, Joo-RanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thakur, MeghnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Skinner, CindyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aschenbach, LaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smirin-Yosef, PolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Har-Zahav, AdiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frommolt, PeterUNSPECIFIEDorcid.org/0000-0002-1966-8014UNSPECIFIED
Hofmann, KayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Konen, OsnatUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Munnich, ArnoldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwartz, Charles E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gothelf, DoronUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Colleaux, LaurenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dever, Thomas E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kubisch, ChristianUNSPECIFIEDorcid.org/0000-0003-4220-0978UNSPECIFIED
Basel-Vanagaite, LinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-478358
DOI: 10.1016/j.molcel.2012.09.005
Journal or Publication Title: Mol. Cell
Volume: 48
Number: 4
Page Range: S. 641 - 647
Date: 2012
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1097-2765
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
VANISHING WHITE-MATTER; START CODON SELECTION; SACCHAROMYCES-CEREVISIAE; SYNAPTIC PLASTICITY; GAMMA-SUBUNIT; LEUKOENCEPHALOPATHY; EXPRESSION; MECHANISM; SYSTEM; MEMORYMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/47835

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