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6caj

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Electron cryo-microscopy of the eukaryotic translation initiation factor 2B from Homo sapiens

6caj, resolution 2.80Å

Structural highlights

6caj is a 10 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	EIF2B5, EIF2BE (HUMAN), EIF2B3 (HUMAN), EIF2B1, EIF2BA (HUMAN), EIF2B2, EIF2BB (HUMAN), EIF2B4, EIF2BD (HUMAN)
Experimental data:	Check to display Experimental Data
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[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. [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] [EI2BA_HUMAN] Cree leukoencephalopathy;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. [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.

Function

[EI2BB_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. [EI2BA_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. [EI2BD_HUMAN] Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP.

Publication Abstract from PubMed

Regulation by the integrated stress response (ISR) converges on the phosphorylation of translation initiation factor eIF2 in response to a variety of stresses. Phosphorylation converts eIF2 from a substrate to a competitive inhibitor of its dedicated guanine nucleotide exchange factor, eIF2B, thereby inhibiting translation. ISRIB, a drug-like eIF2B activator, reverses the effects of eIF2 phosphorylation, and in rodents it enhances cognition and corrects cognitive deficits after brain injury. To determine its mechanism of action, we solved an atomic-resolution structure of ISRIB bound in a deep cleft within decameric human eIF2B by cryo-electron microscopy. Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of two identical tetrameric subcomplexes, and ISRIB promoted this step by cross-bridging a central symmetry interface. Thus, regulation of eIF2B assembly emerges as a rheostat for eIF2B activity that tunes translation during the ISR and that can be further modulated by ISRIB.

Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule.,Tsai JC, Miller-Vedam LE, Anand AA, Jaishankar P, Nguyen HC, Renslo AR, Frost A, Walter P Science. 2018 Mar 30;359(6383). pii: 359/6383/eaaq0939. doi:, 10.1126/science.aaq0939. PMID:29599213^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Tsai JC, Miller-Vedam LE, Anand AA, Jaishankar P, Nguyen HC, Renslo AR, Frost A, Walter P. Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule. Science. 2018 Mar 30;359(6383). pii: 359/6383/eaaq0939. doi:, 10.1126/science.aaq0939. PMID:29599213 doi:http://dx.doi.org/10.1126/science.aaq0939

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6caj"

@@ Line 1: / Line 1: @@
 ==Electron cryo-microscopy of the eukaryotic translation initiation factor 2B from Homo sapiens==
-<StructureSection load='6caj' size='340' side='right'caption='[[6caj]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
+<SX load='6caj' size='340' side='right' viewer='molstar' caption='[[6caj]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6caj]] is a 10 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CAJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CAJ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6caj]] is a 10 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CAJ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6CAJ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C7B:2-(4-chloranylphenoxy)-~{N}-[4-[2-(4-chloranylphenoxy)ethanoylamino]cyclohexyl]ethanamide'>C7B</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C7B:2-(4-chloranylphenoxy)-~{N}-[4-[2-(4-chloranylphenoxy)ethanoylamino]cyclohexyl]ethanamide'>C7B</scene></td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EIF2B5, EIF2BE ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), EIF2B3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), EIF2B1, EIF2BA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), EIF2B2, EIF2BB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), EIF2B4, EIF2BD ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6caj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6caj OCA], [http://pdbe.org/6caj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6caj RCSB], [http://www.ebi.ac.uk/pdbsum/6caj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6caj ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6caj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6caj OCA], [http://pdbe.org/6caj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6caj RCSB], [http://www.ebi.ac.uk/pdbsum/6caj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6caj ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 24: / Line 24: @@
 <references/>
 __TOC__
-</StructureSection>
+</SX>
 [[Category: Human]]
 [[Category: Large Structures]]

6caj

From Proteopedia

Current revision

Electron cryo-microscopy of the eukaryotic translation initiation factor 2B from Homo sapiens

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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