Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation

  1. Matthew C Johnson
  2. Justin M Kollman  Is a corresponding author
  1. University of Washington, United States

Abstract

Inosine monophosphate dehydrogenase (IMPDH) mediates the first committed step in guanine nucleotide biosynthesis and plays important roles in cellular proliferation and the immune response. IMPDH reversibly polymerizes in cells and tissues in response to changes in metabolic demand. Self-assembly of metabolic enzymes is increasingly recognized as a general mechanism for regulating activity, typically by stabilizing specific conformations of an enzyme, but the regulatory role of IMPDH filaments has remained unclear. Here, we report a series of human IMPDH2 cryo-EM structures in both active and inactive conformations. The structures define the mechanism of filament assembly, and reveal how filament-dependent allosteric regulation of IMPDH2 makes the enzyme less sensitive to feedback inhibition, explaining why assembly occurs under physiological conditions that require expansion of guanine nucleotide pools. Tuning sensitivity to an allosteric inhibitor distinguishes IMPDH from other metabolic filaments, and highlights the diversity of regulatory outcomes that can emerge from self-assembly.

Data availability

The cryo-EM maps described here have been deposited in the Electron Microscopy Data Bank with accession numbers 20687, 20688, 20690, 20691, 20701, 20704, 20705, 20706, 20707, 20709, 20716, 20718, 20720, 20722, 20723, 20725, 20742, 20741, and 20743. The refined atomic coordinates have been deposited in the Protein Data Bank with accession numbers 6U8E, 6U8N, 6U8R, 6U8S, 6U9O, 6UA2, 6UA4, 6UA5, 6UAJ, 6UC2, 6UDP, 6UDO, and 6UDQ.

The following data sets were generated

Article and author information

Author details

  1. Matthew C Johnson

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1477-7801
  2. Justin M Kollman

    Department of Biochemistry, University of Washington, Seattle, United States
    For correspondence
    jkoll@uw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0350-5827

Funding

National Institutes of Health (5R01GM118396-04)

  • Justin M Kollman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Sjors HW Scheres, MRC Laboratory of Molecular Biology, United Kingdom

Publication history

  1. Received: November 1, 2019
  2. Accepted: January 29, 2020
  3. Accepted Manuscript published: January 30, 2020 (version 1)
  4. Version of Record published: February 13, 2020 (version 2)

Copyright

© 2020, Johnson & Kollman

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Matthew C Johnson
  2. Justin M Kollman
(2020)
Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation
eLife 9:e53243.
https://doi.org/10.7554/eLife.53243

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