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Structural Characterization of Hypoxia Inducible Factor α—Prolyl Hydroxylase Domain 2 Interaction through MD Simulations
The Prolyl Hydroxylases (PHDs) are an enzymatic family that regulates cell oxygen-sensing. PHDs hydroxylate hypoxia-inducible transcription factors α (HIFs-α) driving their proteasomal degradation. Hypoxia inhibits PHDs activity, inducing HIFs-α stabilization and cell adaptation to hypoxia. As a hal...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10003257/ https://www.ncbi.nlm.nih.gov/pubmed/36902141 http://dx.doi.org/10.3390/ijms24054710 |
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author | Camagni, Giorgia F. Minervini, Giovanni Tosatto, Silvio C. E. |
author_facet | Camagni, Giorgia F. Minervini, Giovanni Tosatto, Silvio C. E. |
author_sort | Camagni, Giorgia F. |
collection | PubMed |
description | The Prolyl Hydroxylases (PHDs) are an enzymatic family that regulates cell oxygen-sensing. PHDs hydroxylate hypoxia-inducible transcription factors α (HIFs-α) driving their proteasomal degradation. Hypoxia inhibits PHDs activity, inducing HIFs-α stabilization and cell adaptation to hypoxia. As a hallmark of cancer, hypoxia promotes neo-angiogenesis and cell proliferation. PHD isoforms are thought to have a variable impact on tumor progression. All isoforms hydroxylate HIF-α (HIF-1,2,3α) with different affinities. However, what determines these differences and how they pair with tumor growth is poorly understood. Here, molecular dynamics simulations were used to characterize the PHD2 binding properties in complexes with HIF-1α and HIF-2α. In parallel, conservation analysis and binding free energy calculations were performed to better understand PHD2 substrate affinity. Our data suggest a direct association between the PHD2 C-terminus and HIF-2α that is not observed in the PHD2/HIF-1α complex. Furthermore, our results indicate that phosphorylation of a PHD2 residue, Thr405, causes a variation in binding energy, despite the fact that this PTM has only a limited structural impact on PHD2/HIFs-α complexes. Collectively, our findings suggest that the PHD2 C-terminus may act as a molecular regulator of PHD’s activity. |
format | Online Article Text |
id | pubmed-10003257 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-100032572023-03-11 Structural Characterization of Hypoxia Inducible Factor α—Prolyl Hydroxylase Domain 2 Interaction through MD Simulations Camagni, Giorgia F. Minervini, Giovanni Tosatto, Silvio C. E. Int J Mol Sci Article The Prolyl Hydroxylases (PHDs) are an enzymatic family that regulates cell oxygen-sensing. PHDs hydroxylate hypoxia-inducible transcription factors α (HIFs-α) driving their proteasomal degradation. Hypoxia inhibits PHDs activity, inducing HIFs-α stabilization and cell adaptation to hypoxia. As a hallmark of cancer, hypoxia promotes neo-angiogenesis and cell proliferation. PHD isoforms are thought to have a variable impact on tumor progression. All isoforms hydroxylate HIF-α (HIF-1,2,3α) with different affinities. However, what determines these differences and how they pair with tumor growth is poorly understood. Here, molecular dynamics simulations were used to characterize the PHD2 binding properties in complexes with HIF-1α and HIF-2α. In parallel, conservation analysis and binding free energy calculations were performed to better understand PHD2 substrate affinity. Our data suggest a direct association between the PHD2 C-terminus and HIF-2α that is not observed in the PHD2/HIF-1α complex. Furthermore, our results indicate that phosphorylation of a PHD2 residue, Thr405, causes a variation in binding energy, despite the fact that this PTM has only a limited structural impact on PHD2/HIFs-α complexes. Collectively, our findings suggest that the PHD2 C-terminus may act as a molecular regulator of PHD’s activity. MDPI 2023-03-01 /pmc/articles/PMC10003257/ /pubmed/36902141 http://dx.doi.org/10.3390/ijms24054710 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Camagni, Giorgia F. Minervini, Giovanni Tosatto, Silvio C. E. Structural Characterization of Hypoxia Inducible Factor α—Prolyl Hydroxylase Domain 2 Interaction through MD Simulations |
title | Structural Characterization of Hypoxia Inducible Factor α—Prolyl Hydroxylase Domain 2 Interaction through MD Simulations |
title_full | Structural Characterization of Hypoxia Inducible Factor α—Prolyl Hydroxylase Domain 2 Interaction through MD Simulations |
title_fullStr | Structural Characterization of Hypoxia Inducible Factor α—Prolyl Hydroxylase Domain 2 Interaction through MD Simulations |
title_full_unstemmed | Structural Characterization of Hypoxia Inducible Factor α—Prolyl Hydroxylase Domain 2 Interaction through MD Simulations |
title_short | Structural Characterization of Hypoxia Inducible Factor α—Prolyl Hydroxylase Domain 2 Interaction through MD Simulations |
title_sort | structural characterization of hypoxia inducible factor α—prolyl hydroxylase domain 2 interaction through md simulations |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10003257/ https://www.ncbi.nlm.nih.gov/pubmed/36902141 http://dx.doi.org/10.3390/ijms24054710 |
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