| Structural highlights
Disease
EI2BE_HUMAN Defects in EIF2B5 are a cause of leukodystrophy with vanishing white matter (VWM) [MIM:603896. VWM is a leukodystrophy that occurs mainly in children. Neurological signs include progressive cerebellar ataxia, spasticity, inconstant optic atrophy and relatively preserved mental abilities. The disease is chronic-progressive with, in most individuals, additional episodes of rapid deterioration following febrile infections or minor head trauma. While childhood onset is the most common form of the disorder, some severe forms are apparent at birth. A severe, early-onset form seen among the Cree and Chippewayan populations of Quebec and Manitoba is called Cree leukoencephalopathy. Milder forms may not become evident until adolescence or adulthood. Some females with milder forms of the disease who survive to adolescence exhibit ovarian dysfunction. This variant of the disorder is called ovarioleukodystrophy.[1] [2] [3] [4] [5] [6]
Function
EI2BE_HUMAN Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP.
Publication Abstract from PubMed
The integrated stress response (ISR) tunes the rate of protein synthesis. Control is exerted by phosphorylation of the general translation initiation factor eIF2. eIF2 is a guanosine triphosphatase that becomes activated by eIF2B, a two-fold symmetric and heterodecameric complex that functions as eIF2's dedicated nucleotide exchange factor. Phosphorylation converts eIF2 from a substrate into an inhibitor of eIF2B. We report cryo-electron microscopy structures of eIF2 bound to eIF2B in the dephosphorylated state. The structures reveal that the eIF2B decamer is a static platform upon which one or two flexible eIF2 trimers bind and align with eIF2B's bipartite catalytic centers to catalyze nucleotide exchange. Phosphorylation refolds eIF2alpha, allowing it to contact eIF2B at a different interface and, we surmise, thereby sequestering it into a nonproductive complex.
eIF2B-catalyzed nucleotide exchange and phosphoregulation by the integrated stress response.,Kenner LR, Anand AA, Nguyen HC, Myasnikov AG, Klose CJ, McGeever LA, Tsai JC, Miller-Vedam LE, Walter P, Frost A Science. 2019 May 3;364(6439):491-495. doi: 10.1126/science.aaw2922. PMID:31048491[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Leegwater PA, Vermeulen G, Konst AA, Naidu S, Mulders J, Visser A, Kersbergen P, Mobach D, Fonds D, van Berkel CG, Lemmers RJ, Frants RR, Oudejans CB, Schutgens RB, Pronk JC, van der Knaap MS. Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nat Genet. 2001 Dec;29(4):383-8. PMID:11704758 doi:10.1038/ng764
- ↑ Fogli A, Wong K, Eymard-Pierre E, Wenger J, Bouffard JP, Goldin E, Black DN, Boespflug-Tanguy O, Schiffmann R. Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus. Ann Neurol. 2002 Oct;52(4):506-10. PMID:12325082 doi:10.1002/ana.10339
- ↑ Fogli A, Rodriguez D, Eymard-Pierre E, Bouhour F, Labauge P, Meaney BF, Zeesman S, Kaneski CR, Schiffmann R, Boespflug-Tanguy O. Ovarian failure related to eukaryotic initiation factor 2B mutations. Am J Hum Genet. 2003 Jun;72(6):1544-50. Epub 2003 Apr 21. PMID:12707859 doi:10.1086/375404
- ↑ Ohlenbusch A, Henneke M, Brockmann K, Goerg M, Hanefeld F, Kohlschutter A, Gartner J. Identification of ten novel mutations in patients with eIF2B-related disorders. Hum Mutat. 2005 Apr;25(4):411. PMID:15776425 doi:10.1002/humu.9325
- ↑ Wu Y, Pan Y, Du L, Wang J, Gu Q, Gao Z, Li J, Leng X, Qin J, Wu X, Jiang Y. Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease. J Hum Genet. 2009 Feb;54(2):74-7. doi: 10.1038/jhg.2008.10. Epub 2009 Jan 16. PMID:19158808 doi:10.1038/jhg.2008.10
- ↑ Matsukawa T, Wang X, Liu R, Wortham NC, Onuki Y, Kubota A, Hida A, Kowa H, Fukuda Y, Ishiura H, Mitsui J, Takahashi Y, Aoki S, Takizawa S, Shimizu J, Goto J, Proud CG, Tsuji S. Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5. Neurogenetics. 2011 Aug;12(3):259-61. doi: 10.1007/s10048-011-0284-7. Epub 2011, Apr 12. PMID:21484434 doi:10.1007/s10048-011-0284-7
- ↑ Kenner LR, Anand AA, Nguyen HC, Myasnikov AG, Klose CJ, McGeever LA, Tsai JC, Miller-Vedam LE, Walter P, Frost A. eIF2B-catalyzed nucleotide exchange and phosphoregulation by the integrated stress response. Science. 2019 May 3;364(6439):491-495. doi: 10.1126/science.aaw2922. PMID:31048491 doi:http://dx.doi.org/10.1126/science.aaw2922
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