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Structural basis of eIF2B-catalyzed GDP exchange and phosphoregulation by the integrated stress response

View ORCID ProfileAditya A. Anand, Lillian R. Kenner, Henry C. Nguyen, Alexander G. Myasnikov, Carolin J. Klose, Lea A. McGeever, Jordan C. Tsai, Lakshmi E. Miller-Vedam, Peter Walter, Adam Frost
doi: https://doi.org/10.1101/504654
Aditya A. Anand
1Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA
2Howard Hughes Medical Institute
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  • ORCID record for Aditya A. Anand
Lillian R. Kenner
1Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA
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Henry C. Nguyen
1Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA
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Alexander G. Myasnikov
1Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA
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Carolin J. Klose
1Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA
2Howard Hughes Medical Institute
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Lea A. McGeever
1Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA
2Howard Hughes Medical Institute
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Jordan C. Tsai
1Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA
2Howard Hughes Medical Institute
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Lakshmi E. Miller-Vedam
1Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA
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Peter Walter
1Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA
2Howard Hughes Medical Institute
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  • For correspondence: peter@walterlab.ucsf.edu adam.frost@ucsf.edu
Adam Frost
1Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA
3Chan Zuckerberg Biohub, San Francisco, CA, USA
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  • For correspondence: peter@walterlab.ucsf.edu adam.frost@ucsf.edu
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Abstract

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 GTPase, 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 cryoEM 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 guanine nucleotide exchange. Phosphorylation refolds eIF2, allowing it to contact eIF2B at a different interface and, we surmise, thereby sequesters it into a non-productive complex.

One Sentence Summary Structures of translation factors eIF2 and eIF2B reveal the mechanism of nucleotide exchange and its phosphoregulation during stress.

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Posted December 22, 2018.
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Structural basis of eIF2B-catalyzed GDP exchange and phosphoregulation by the integrated stress response
Aditya A. Anand, Lillian R. Kenner, Henry C. Nguyen, Alexander G. Myasnikov, Carolin J. Klose, Lea A. McGeever, Jordan C. Tsai, Lakshmi E. Miller-Vedam, Peter Walter, Adam Frost
bioRxiv 504654; doi: https://doi.org/10.1101/504654
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Structural basis of eIF2B-catalyzed GDP exchange and phosphoregulation by the integrated stress response
Aditya A. Anand, Lillian R. Kenner, Henry C. Nguyen, Alexander G. Myasnikov, Carolin J. Klose, Lea A. McGeever, Jordan C. Tsai, Lakshmi E. Miller-Vedam, Peter Walter, Adam Frost
bioRxiv 504654; doi: https://doi.org/10.1101/504654

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