GSTDTAP  > 地球科学
DOI10.1126/science.aaq0939
Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule
Tsai, Jordan C.1,2; Miller-Vedam, Lakshmi E.2,3; Anand, Aditya A.1,2; Jaishankar, Priyadarshini4,5; Nguyen, Henry C.2,3; Renslo, Adam R.4,5; Frost, Adam2,3; Walter, Peter1,2
2018-03-30
发表期刊SCIENCE
ISSN0036-8075
EISSN1095-9203
出版年2018
卷号359期号:6383页码:1483-+
文章类型Article
语种英语
国家USA
英文摘要

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.


领域地球科学 ; 气候变化 ; 资源环境
收录类别SCI-E
WOS记录号WOS:000428657000036
WOS关键词INITIATION-FACTOR EIF2B ; ALPHA-SUBUNIT ; REGULATORY SUBCOMPLEX ; TRANSLATIONAL CONTROL ; CRYSTAL-STRUCTURE ; INHIBITION ; ARCHITECTURE ; EIF2-ALPHA ; INSIGHTS ; COMPLEX
WOS类目Multidisciplinary Sciences
WOS研究方向Science & Technology - Other Topics
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文献类型期刊论文
条目标识符http://119.78.100.173/C666/handle/2XK7JSWQ/198296
专题地球科学
资源环境科学
气候变化
作者单位1.Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA;
2.Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA;
3.Chan Zuckerberg Biohub, San Francisco, CA 94158 USA;
4.Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA USA;
5.Univ Calif San Francisco, Small Mol Discovery Ctr, San Francisco, CA 94143 USA
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Tsai, Jordan C.,Miller-Vedam, Lakshmi E.,Anand, Aditya A.,et al. Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule[J]. SCIENCE,2018,359(6383):1483-+.
APA Tsai, Jordan C..,Miller-Vedam, Lakshmi E..,Anand, Aditya A..,Jaishankar, Priyadarshini.,Nguyen, Henry C..,...&Walter, Peter.(2018).Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule.SCIENCE,359(6383),1483-+.
MLA Tsai, Jordan C.,et al."Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule".SCIENCE 359.6383(2018):1483-+.
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