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Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B.

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Title: Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B.
Authors: Zyryanova, Alisa F. (AUTHOR), Weis, Félix (AUTHOR), Faille, Alexandre (AUTHOR), Abo Alard, Akeel (AUTHOR), Crespillo-Casado, Ana (AUTHOR), Sekine, Yusuke (AUTHOR), Harding, Heather P. (AUTHOR), Allen, Felicity (AUTHOR), Part, Leopold (AUTHOR), Fromont, Christophe (AUTHOR), Fischer, Peter M. (AUTHOR), Warren, Alan J. (AUTHOR), Ron, David (AUTHOR)
Source: Science (pre-March 2025). 3/30/2018, Vol. 359 Issue 6383, p1533-1536. 4p. 3 Diagrams.
Subjects: Translation initiation factors (Biochemistry), Guanine nucleotide exchange factors, Phosphorylation, Neurodegeneration, Mutagenesis, Prevention
Abstract: The integrated stress response (ISR) is a conserved translational and transcriptional program affecting metabolism, memory, and immunity. The ISR is mediated by stress-induced phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) that attenuates the guanine nucleotide exchange factor eIF2B. A chemical inhibitor of the ISR, ISRIB, reverses the attenuation of eIF2B by phosphorylated eIF2α, protecting mice from neurodegeneration and traumatic brain injury. We describe a 4.1-angstrom-resolution cryo-electron microscopy structure of human eIF2B with an ISRIB molecule bound at the interface between the b and d regulatory subunits. Mutagenesis of residues lining this pocket altered the hierarchical cellular response to ISRIB analogs in vivo and ISRIB binding in vitro. Our findings point to a site in eIF2B that can be exploited by ISRIB to regulate translation. [ABSTRACT FROM AUTHOR]
Copyright of Science (pre-March 2025) is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B.
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  Data: <searchLink fieldCode="AR" term="%22Zyryanova%2C+Alisa+F%2E%22">Zyryanova, Alisa F.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Weis%2C+Félix%22">Weis, Félix</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Faille%2C+Alexandre%22">Faille, Alexandre</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Abo+Alard%2C+Akeel%22">Abo Alard, Akeel</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Crespillo-Casado%2C+Ana%22">Crespillo-Casado, Ana</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Sekine%2C+Yusuke%22">Sekine, Yusuke</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Harding%2C+Heather+P%2E%22">Harding, Heather P.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Allen%2C+Felicity%22">Allen, Felicity</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Part%2C+Leopold%22">Part, Leopold</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Fromont%2C+Christophe%22">Fromont, Christophe</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Fischer%2C+Peter+M%2E%22">Fischer, Peter M.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Warren%2C+Alan+J%2E%22">Warren, Alan J.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ron%2C+David%22">Ron, David</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Science+%28pre-March+2025%29%22">Science (pre-March 2025)</searchLink>. 3/30/2018, Vol. 359 Issue 6383, p1533-1536. 4p. 3 Diagrams.
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  Data: <searchLink fieldCode="DE" term="%22Translation+initiation+factors+%28Biochemistry%29%22">Translation initiation factors (Biochemistry)</searchLink><br /><searchLink fieldCode="DE" term="%22Guanine+nucleotide+exchange+factors%22">Guanine nucleotide exchange factors</searchLink><br /><searchLink fieldCode="DE" term="%22Phosphorylation%22">Phosphorylation</searchLink><br /><searchLink fieldCode="DE" term="%22Neurodegeneration%22">Neurodegeneration</searchLink><br /><searchLink fieldCode="DE" term="%22Mutagenesis%22">Mutagenesis</searchLink><br /><searchLink fieldCode="DE" term="%22Prevention%22">Prevention</searchLink>
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  Data: The integrated stress response (ISR) is a conserved translational and transcriptional program affecting metabolism, memory, and immunity. The ISR is mediated by stress-induced phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) that attenuates the guanine nucleotide exchange factor eIF2B. A chemical inhibitor of the ISR, ISRIB, reverses the attenuation of eIF2B by phosphorylated eIF2α, protecting mice from neurodegeneration and traumatic brain injury. We describe a 4.1-angstrom-resolution cryo-electron microscopy structure of human eIF2B with an ISRIB molecule bound at the interface between the b and d regulatory subunits. Mutagenesis of residues lining this pocket altered the hierarchical cellular response to ISRIB analogs in vivo and ISRIB binding in vitro. Our findings point to a site in eIF2B that can be exploited by ISRIB to regulate translation. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
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  Data: <i>Copyright of Science (pre-March 2025) is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1126/science.aar5129
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        Text: English
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        PageCount: 4
        StartPage: 1533
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      – SubjectFull: Translation initiation factors (Biochemistry)
        Type: general
      – SubjectFull: Guanine nucleotide exchange factors
        Type: general
      – SubjectFull: Phosphorylation
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      – SubjectFull: Neurodegeneration
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      – SubjectFull: Prevention
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      – TitleFull: Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B.
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              Text: 3/30/2018
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