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

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 eIF2ß 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 eIF2ß. 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.

Onset of three-centre, four-electron bonding in peri-substituted acenaphthenes: a structural and computational investigation.

Two series of sterically crowded peri-substituted acenaphthenes have been prepared, containing mixed halogen-chalcogen functionalities at the 5,6-positions in A1-A6 (Acenap[X][EPh] (Acenap = acenaphthene-5,6-diyl; X = Br, I; E = S, Se, Te) and chalcogen-chalcogen moieties in A7-A12 (Acenap[EPh][E'Ph] (Acenap = acenaphthene-5,6-diyl; E/E' = S, Se, Te). The related dihalide compounds A13-A16 Acenap[XX'] (XX' = BrBr, II, IBr, ClCl) have also been prepared. Distortion of the acenaphthene framework away from the ideal was studied as a function of the steric bulk of the interacting halogen and chalcogen atoms occupying the peri-positions. The acenaphthene series experiences a general increase in peri-separation for molecules accommodating heavier congeners and maps the trends observed previously for the analogous naphthalene compounds N1-N12 (Nap[X][EPh], Nap[EPh][E'Ph] (X = Br, I; E/E' = S, Se, Te). The conformation of the aromatic ring systems and subsequent location of p-type lone-pairs dominates the geometry of the peri-region. The differences in peri-separations observed for compounds adopting differing conformations of the peri-substituted phenyl group can be correlated to the ability of the frontier orbitals of the halogen or chalcogen atoms to take part in attractive or repulsive interactions. Density-functional studies have confirmed these interactions and suggested the onset of formation of three-centre, four-electron bonding under appropriate geometric conditions.