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

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...

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Autores principales: Johnson, Matthew C, Kollman, Justin M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018514/
https://www.ncbi.nlm.nih.gov/pubmed/31999252
http://dx.doi.org/10.7554/eLife.53243
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author Johnson, Matthew C
Kollman, Justin M
author_facet Johnson, Matthew C
Kollman, Justin M
author_sort Johnson, Matthew C
collection PubMed
description 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.
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spelling pubmed-70185142020-02-18 Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation Johnson, Matthew C Kollman, Justin M eLife Structural Biology and Molecular Biophysics 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. eLife Sciences Publications, Ltd 2020-01-30 /pmc/articles/PMC7018514/ /pubmed/31999252 http://dx.doi.org/10.7554/eLife.53243 Text en © 2020, Johnson and Kollman http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Structural Biology and Molecular Biophysics
Johnson, Matthew C
Kollman, Justin M
Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation
title Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation
title_full Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation
title_fullStr Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation
title_full_unstemmed Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation
title_short Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation
title_sort cryo-em structures demonstrate human impdh2 filament assembly tunes allosteric regulation
topic Structural Biology and Molecular Biophysics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018514/
https://www.ncbi.nlm.nih.gov/pubmed/31999252
http://dx.doi.org/10.7554/eLife.53243
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