Mutations Linked to Leukoencephalopathy with Vanishing White Matter Impair the Function of the Eukaryotic Initiation Factor 2B Complex in Diverse Ways
- 1 April 2004
- journal article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 24 (8), 3295-306
- https://doi.org/10.1128/mcb.24.8.3295-3306.2004
Abstract
Leukoencephalopathy with vanishing white matter (VWM) is a severe inherited human neurodegenerative disorder that is caused by mutations in the genes for the subunits of eukaryotic initiation factor 2B (eIF2B), a heteropentameric guanine nucleotide exchange factor that regulates both global and mRNA-specific translation. Marked variability is evident in the clinical severity and time course of VWM in patients. Here we have studied the effects of VWM mutations on the function of human eIF2B. All the mutations tested cause partial loss of activity. Frameshift mutations in genes for eIF2Bepsilon or eIF2Bbeta lead to truncated polypeptides that fail to form complexes with the other subunits and are effectively null mutations. Certain point mutations also impair the ability of eIF2Bbeta or -epsilon to form eIF2B holocomplexes and also diminish the intrinsic nucleotide exchange activity of eIF2B. A point mutation in the catalytic domain of eIF2Bepsilon impairs its ability to bind the substrate, while two mutations in eIF2Bbeta actually enhance eIF2 binding. We provide evidence that expression of VWM mutant eIF2B may enhance the translation of specific mRNAs. The variability of the clinical phenotype in VWM may reflect the multiple ways in which VWM mutations affect eIF2B function.Keywords
This publication has 38 references indexed in Scilit:
- Phosphorylation of the α Subunit of Eukaryotic Initiation Factor 2 Is Required for Activation of NF-κB in Response to Diverse Cellular StressesMolecular and Cellular Biology, 2003
- An Integrated Stress Response Regulates Amino Acid Metabolism and Resistance to Oxidative StressMolecular Cell, 2003
- Evidence that the dephosphorylation of Ser535 in the ∊-subunit of eukaryotic initiation factor (eIF) 2B is insufficient for the activation of eIF2B by insulinBiochemical Journal, 2002
- Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locusAnnals of Neurology, 2002
- Tight Binding of the Phosphorylated α Subunit of Initiation Factor 2 (eIF2α) to the Regulatory Subunits of Guanine Nucleotide Exchange Factor eIF2B Is Required for Inhibition of Translation InitiationMolecular and Cellular Biology, 2001
- Upregulation of iNOS Expression and Phosphorylation of eIF-2αAre Paralleled by Suppression of Protein Synthesis in Rat Hypothalamus in a Closed Head Trauma ModelJournal of Neurotrauma, 2001
- Eukaryotic Initiation Factors 4A (eIF4A) and 4G (eIF4G) Mutually Interact in a 1:1 Ratio in VivoOnline Journal of Public Health Informatics, 2001
- The Gene for Leukoencephalopathy with Vanishing White Matter Is Located on Chromosome 3q27American Journal of Human Genetics, 1999
- The α-Subunit of the Mammalian Guanine Nucleotide-Exchange Factor eIF-2B Is Essential for Catalytic Activity in VitroBiochemical and Biophysical Research Communications, 1996
- Multidomain organization of eukaryotic guanine nucleotide exchange translation initiation factor eIF‐2B subunits revealed by analysis of conserved sequence motifsProtein Science, 1995