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Inositol pyrophosphates activate the vacuolar transport chaperone complex in yeast by disrupting a homotypic SPX domain interaction
Many proteins involved in eukaryotic phosphate homeostasis are regulated by SPX domains. In yeast, the vacuolar transporter chaperone (VTC) complex contains two such domains, but mechanistic details of its regulation are not well understood. Here, we show at the atomic level how inositol pyrophospha...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10167327/ https://www.ncbi.nlm.nih.gov/pubmed/37156835 http://dx.doi.org/10.1038/s41467-023-38315-w |
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author | Pipercevic, Joka Kohl, Bastian Gerasimaite, Ruta Comte-Miserez, Véronique Hostachy, Sarah Müntener, Thomas Agustoni, Elia Jessen, Henning Jacob Fiedler, Dorothea Mayer, Andreas Hiller, Sebastian |
author_facet | Pipercevic, Joka Kohl, Bastian Gerasimaite, Ruta Comte-Miserez, Véronique Hostachy, Sarah Müntener, Thomas Agustoni, Elia Jessen, Henning Jacob Fiedler, Dorothea Mayer, Andreas Hiller, Sebastian |
author_sort | Pipercevic, Joka |
collection | PubMed |
description | Many proteins involved in eukaryotic phosphate homeostasis are regulated by SPX domains. In yeast, the vacuolar transporter chaperone (VTC) complex contains two such domains, but mechanistic details of its regulation are not well understood. Here, we show at the atomic level how inositol pyrophosphates interact with SPX domains of subunits Vtc2 and Vtc3 to control the activity of the VTC complex. Vtc2 inhibits the catalytically active VTC subunit Vtc4 by homotypic SPX–SPX interactions via the conserved helix α1 and the previously undescribed helix α7. Binding of inositol pyrophosphates to Vtc2 abrogates this interaction, thus activating the VTC complex. Accordingly, VTC activation is also achieved by site-specific point mutations that disrupt the SPX–SPX interface. Structural data suggest that ligand binding induces reorientation of helix α1 and exposes the modifiable helix α7, which might facilitate its post-translational modification in vivo. The variable composition of these regions within the SPX domain family might contribute to the diversified SPX functions in eukaryotic phosphate homeostasis. |
format | Online Article Text |
id | pubmed-10167327 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-101673272023-05-10 Inositol pyrophosphates activate the vacuolar transport chaperone complex in yeast by disrupting a homotypic SPX domain interaction Pipercevic, Joka Kohl, Bastian Gerasimaite, Ruta Comte-Miserez, Véronique Hostachy, Sarah Müntener, Thomas Agustoni, Elia Jessen, Henning Jacob Fiedler, Dorothea Mayer, Andreas Hiller, Sebastian Nat Commun Article Many proteins involved in eukaryotic phosphate homeostasis are regulated by SPX domains. In yeast, the vacuolar transporter chaperone (VTC) complex contains two such domains, but mechanistic details of its regulation are not well understood. Here, we show at the atomic level how inositol pyrophosphates interact with SPX domains of subunits Vtc2 and Vtc3 to control the activity of the VTC complex. Vtc2 inhibits the catalytically active VTC subunit Vtc4 by homotypic SPX–SPX interactions via the conserved helix α1 and the previously undescribed helix α7. Binding of inositol pyrophosphates to Vtc2 abrogates this interaction, thus activating the VTC complex. Accordingly, VTC activation is also achieved by site-specific point mutations that disrupt the SPX–SPX interface. Structural data suggest that ligand binding induces reorientation of helix α1 and exposes the modifiable helix α7, which might facilitate its post-translational modification in vivo. The variable composition of these regions within the SPX domain family might contribute to the diversified SPX functions in eukaryotic phosphate homeostasis. Nature Publishing Group UK 2023-05-08 /pmc/articles/PMC10167327/ /pubmed/37156835 http://dx.doi.org/10.1038/s41467-023-38315-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Pipercevic, Joka Kohl, Bastian Gerasimaite, Ruta Comte-Miserez, Véronique Hostachy, Sarah Müntener, Thomas Agustoni, Elia Jessen, Henning Jacob Fiedler, Dorothea Mayer, Andreas Hiller, Sebastian Inositol pyrophosphates activate the vacuolar transport chaperone complex in yeast by disrupting a homotypic SPX domain interaction |
title | Inositol pyrophosphates activate the vacuolar transport chaperone complex in yeast by disrupting a homotypic SPX domain interaction |
title_full | Inositol pyrophosphates activate the vacuolar transport chaperone complex in yeast by disrupting a homotypic SPX domain interaction |
title_fullStr | Inositol pyrophosphates activate the vacuolar transport chaperone complex in yeast by disrupting a homotypic SPX domain interaction |
title_full_unstemmed | Inositol pyrophosphates activate the vacuolar transport chaperone complex in yeast by disrupting a homotypic SPX domain interaction |
title_short | Inositol pyrophosphates activate the vacuolar transport chaperone complex in yeast by disrupting a homotypic SPX domain interaction |
title_sort | inositol pyrophosphates activate the vacuolar transport chaperone complex in yeast by disrupting a homotypic spx domain interaction |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10167327/ https://www.ncbi.nlm.nih.gov/pubmed/37156835 http://dx.doi.org/10.1038/s41467-023-38315-w |
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