Cargando…
Loss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis
Glutamine fructose-6-phosphate amidotransferase (GFAT) is the key enzyme in the hexosamine pathway (HP) that produces uridine 5′-diphospho-N-acetyl-d-glucosamine (UDP-GlcNAc), linking energy metabolism with posttranslational protein glycosylation. In Caenorhabditis elegans, we previously identified...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000685/ https://www.ncbi.nlm.nih.gov/pubmed/32019926 http://dx.doi.org/10.1038/s41467-020-14524-5 |
_version_ | 1783494085906006016 |
---|---|
author | Ruegenberg, Sabine Horn, Moritz Pichlo, Christian Allmeroth, Kira Baumann, Ulrich Denzel, Martin S. |
author_facet | Ruegenberg, Sabine Horn, Moritz Pichlo, Christian Allmeroth, Kira Baumann, Ulrich Denzel, Martin S. |
author_sort | Ruegenberg, Sabine |
collection | PubMed |
description | Glutamine fructose-6-phosphate amidotransferase (GFAT) is the key enzyme in the hexosamine pathway (HP) that produces uridine 5′-diphospho-N-acetyl-d-glucosamine (UDP-GlcNAc), linking energy metabolism with posttranslational protein glycosylation. In Caenorhabditis elegans, we previously identified gfat-1 gain-of-function mutations that elevate UDP-GlcNAc levels, improve protein homeostasis, and extend lifespan. GFAT is highly conserved, but the gain-of-function mechanism and its relevance in mammalian cells remained unclear. Here, we present the full-length crystal structure of human GFAT-1 in complex with various ligands and with important mutations. UDP-GlcNAc directly interacts with GFAT-1, inhibiting catalytic activity. The longevity-associated G451E variant shows drastically reduced sensitivity to UDP-GlcNAc inhibition in enzyme activity assays. Our structural and functional data point to a critical role of the interdomain linker in UDP-GlcNAc inhibition. In mammalian cells, the G451E variant potently activates the HP. Therefore, GFAT-1 gain-of-function through loss of feedback inhibition constitutes a potential target for the treatment of age-related proteinopathies. |
format | Online Article Text |
id | pubmed-7000685 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-70006852020-02-06 Loss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis Ruegenberg, Sabine Horn, Moritz Pichlo, Christian Allmeroth, Kira Baumann, Ulrich Denzel, Martin S. Nat Commun Article Glutamine fructose-6-phosphate amidotransferase (GFAT) is the key enzyme in the hexosamine pathway (HP) that produces uridine 5′-diphospho-N-acetyl-d-glucosamine (UDP-GlcNAc), linking energy metabolism with posttranslational protein glycosylation. In Caenorhabditis elegans, we previously identified gfat-1 gain-of-function mutations that elevate UDP-GlcNAc levels, improve protein homeostasis, and extend lifespan. GFAT is highly conserved, but the gain-of-function mechanism and its relevance in mammalian cells remained unclear. Here, we present the full-length crystal structure of human GFAT-1 in complex with various ligands and with important mutations. UDP-GlcNAc directly interacts with GFAT-1, inhibiting catalytic activity. The longevity-associated G451E variant shows drastically reduced sensitivity to UDP-GlcNAc inhibition in enzyme activity assays. Our structural and functional data point to a critical role of the interdomain linker in UDP-GlcNAc inhibition. In mammalian cells, the G451E variant potently activates the HP. Therefore, GFAT-1 gain-of-function through loss of feedback inhibition constitutes a potential target for the treatment of age-related proteinopathies. Nature Publishing Group UK 2020-02-04 /pmc/articles/PMC7000685/ /pubmed/32019926 http://dx.doi.org/10.1038/s41467-020-14524-5 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Ruegenberg, Sabine Horn, Moritz Pichlo, Christian Allmeroth, Kira Baumann, Ulrich Denzel, Martin S. Loss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis |
title | Loss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis |
title_full | Loss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis |
title_fullStr | Loss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis |
title_full_unstemmed | Loss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis |
title_short | Loss of GFAT-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis |
title_sort | loss of gfat-1 feedback regulation activates the hexosamine pathway that modulates protein homeostasis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000685/ https://www.ncbi.nlm.nih.gov/pubmed/32019926 http://dx.doi.org/10.1038/s41467-020-14524-5 |
work_keys_str_mv | AT ruegenbergsabine lossofgfat1feedbackregulationactivatesthehexosaminepathwaythatmodulatesproteinhomeostasis AT hornmoritz lossofgfat1feedbackregulationactivatesthehexosaminepathwaythatmodulatesproteinhomeostasis AT pichlochristian lossofgfat1feedbackregulationactivatesthehexosaminepathwaythatmodulatesproteinhomeostasis AT allmerothkira lossofgfat1feedbackregulationactivatesthehexosaminepathwaythatmodulatesproteinhomeostasis AT baumannulrich lossofgfat1feedbackregulationactivatesthehexosaminepathwaythatmodulatesproteinhomeostasis AT denzelmartins lossofgfat1feedbackregulationactivatesthehexosaminepathwaythatmodulatesproteinhomeostasis |