6o9z

Structural highlights

Disease

[EI2BA_HUMAN] Cree leukoencephalopathy;Late infantile CACH syndrome;Ovarioleukodystrophy. The disease is caused by mutations affecting the gene represented in this entry. [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]} [EI2BD_HUMAN] Juvenile or adult CACH syndrome;Congenital or early infantile CACH syndrome;Cree leukoencephalopathy;Late infantile CACH syndrome;Ovarioleukodystrophy. The disease is caused by mutations affecting the gene represented in this entry. [EI2BB_HUMAN] Cree leukoencephalopathy;Juvenile or adult CACH syndrome;Congenital or early infantile CACH syndrome;Late infantile CACH syndrome;Ovarioleukodystrophy. The disease is caused by mutations affecting the gene represented in this entry. [EI2BG_HUMAN] Juvenile or adult CACH syndrome;Congenital or early infantile CACH syndrome;Cree leukoencephalopathy;Late infantile CACH syndrome;Ovarioleukodystrophy. The disease is caused by mutations affecting the gene represented in this entry.

Function

[IF2A_HUMAN] Functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA. This complex binds to a 40S ribosomal subunit, followed by mRNA binding to form a 43S preinitiation complex. Junction of the 60S ribosomal subunit to form the 80S initiation complex is preceded by hydrolysis of the GTP bound to eIF-2 and release of an eIF-2-GDP binary complex. In order for eIF-2 to recycle and catalyze another round of initiation, the GDP bound to eIF-2 must exchange with GTP by way of a reaction catalyzed by eIF-2B. [EI2BA_HUMAN] Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. [EI2BE_HUMAN] Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. [EI2BD_HUMAN] Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. [EI2BB_HUMAN] Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. [EI2BG_HUMAN] Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP.

See Also

• Eukaryotic initiation factor 3D structures

References

1. ↑ 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
2. ↑ 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
3. ↑ 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
4. ↑ 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
5. ↑ 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
6. ↑ 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
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