Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule

Jordan C. Tsai, Lakshmi E. Miller-Vedam, Aditya A. Anand, Priyadarshini Jaishankar, Henry C. Nguyen, Adam R. Renslo, Adam Frost, Peter Walter
doi: https://doi.org/10.1101/222257
Jordan C. Tsai
1Howard Hughes Medical Institute
2Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lakshmi E. Miller-Vedam
2Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA
4Chan Zuckerberg Biohub, San Francisco, CA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Aditya A. Anand
1Howard Hughes Medical Institute
2Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Priyadarshini Jaishankar
3Department of Pharmaceutical Chemistry, and Small Molecule Discovery Center, University of California at San Francisco, San Francisco, CA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Henry C. Nguyen
2Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA
4Chan Zuckerberg Biohub, San Francisco, CA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Adam R. Renslo
3Department of Pharmaceutical Chemistry, and Small Molecule Discovery Center, University of California at San Francisco, San Francisco, CA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Adam Frost
2Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA
4Chan Zuckerberg Biohub, San Francisco, CA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: peter@walterlab.ucsf.edu adam.frost@ucsf.edu
Peter Walter
1Howard Hughes Medical Institute
2Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: peter@walterlab.ucsf.edu adam.frost@ucsf.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

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 substrate to competitive inhibitor of its dedicated guanine nucleotide exchange factor, eIF2B, inhibiting translation. ISRIB, a drug-like eIF2B activator, reverses the effects of eIF2 phosphorylation and, remarkably, in rodents 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 electron cryo-microscopy. Structural and biochemical analyses revealed that formation of fully active, decameric eIF2B holoenzyme depended on the assembly of two identical tetrameric subcomplexes, and that ISRIB promoted this step by cross-bridging a central symmetry interface. 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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted November 24, 2017.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule
Jordan C. Tsai, Lakshmi E. Miller-Vedam, Aditya A. Anand, Priyadarshini Jaishankar, Henry C. Nguyen, Adam R. Renslo, Adam Frost, Peter Walter
bioRxiv 222257; doi: https://doi.org/10.1101/222257
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule
Jordan C. Tsai, Lakshmi E. Miller-Vedam, Aditya A. Anand, Priyadarshini Jaishankar, Henry C. Nguyen, Adam R. Renslo, Adam Frost, Peter Walter
bioRxiv 222257; doi: https://doi.org/10.1101/222257

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Biochemistry
Subject Areas
All Articles
  • Animal Behavior and Cognition (3586)
  • Biochemistry (7545)
  • Bioengineering (5495)
  • Bioinformatics (20732)
  • Biophysics (10294)
  • Cancer Biology (7951)
  • Cell Biology (11611)
  • Clinical Trials (138)
  • Developmental Biology (6586)
  • Ecology (10168)
  • Epidemiology (2065)
  • Evolutionary Biology (13580)
  • Genetics (9521)
  • Genomics (12817)
  • Immunology (7906)
  • Microbiology (19503)
  • Molecular Biology (7641)
  • Neuroscience (41982)
  • Paleontology (307)
  • Pathology (1254)
  • Pharmacology and Toxicology (2192)
  • Physiology (3259)
  • Plant Biology (7025)
  • Scientific Communication and Education (1294)
  • Synthetic Biology (1947)
  • Systems Biology (5419)
  • Zoology (1113)