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Assessing the Direct Binding of Ark-Like E3 RING Ligases to Ubiquitin and Its Implication on Their Protein Interaction Network
The ubiquitin pathway required for most proteins’ targeted degradation involves three classes of enzymes: E1-activating enzyme, E2-conjugating enzyme, and E3-ligases. The human Ark2C is the single known E3 ligase that adopts an alternative, Ub-dependent mechanism for the activation of Ub transfer in...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594095/ https://www.ncbi.nlm.nih.gov/pubmed/33086510 http://dx.doi.org/10.3390/molecules25204787 |
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author | Mintis, Dimitris G. Chasapi, Anastasia Poulas, Konstantinos Lagoumintzis, George Chasapis, Christos T. |
author_facet | Mintis, Dimitris G. Chasapi, Anastasia Poulas, Konstantinos Lagoumintzis, George Chasapis, Christos T. |
author_sort | Mintis, Dimitris G. |
collection | PubMed |
description | The ubiquitin pathway required for most proteins’ targeted degradation involves three classes of enzymes: E1-activating enzyme, E2-conjugating enzyme, and E3-ligases. The human Ark2C is the single known E3 ligase that adopts an alternative, Ub-dependent mechanism for the activation of Ub transfer in the pathway. Its RING domain binds both E2-Ub and free Ub with high affinity, resulting in a catalytic active Ub(R)-RING-E2-Ub(D) complex formation. We examined potential changes in the conformational plasticity of the Ark2C RING domain and its ligands in their complexed form within the ubiquitin pathway through molecular dynamics (MD). Three molecular mechanics force fields compared to previous NMR relaxation studies of RING domain of Arkadia were used for effective and accurate assessment of MDs. Our results suggest the Ark2C Ub-RING docking site has a substantial impact on maintaining the conformational rigidity of E2-E3 assembly, necessary for the E3’s catalytic activity. In the Ub(R)-RING-E2-Ub(D) catalytic complex, the Ub(R) molecule was found to have greater mobility than the other Ub, bound to E2. Furthermore, network-based bioinformatics helped us identify E3 RING ligase candidates which potentially exhibit similar structural modules as Ark2C, along with predicted substrates targeted by the Ub-binding RING Ark2C. Our findings could trigger a further exploration of related unrevealed functions of various other E3 RING ligases. |
format | Online Article Text |
id | pubmed-7594095 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75940952020-10-30 Assessing the Direct Binding of Ark-Like E3 RING Ligases to Ubiquitin and Its Implication on Their Protein Interaction Network Mintis, Dimitris G. Chasapi, Anastasia Poulas, Konstantinos Lagoumintzis, George Chasapis, Christos T. Molecules Article The ubiquitin pathway required for most proteins’ targeted degradation involves three classes of enzymes: E1-activating enzyme, E2-conjugating enzyme, and E3-ligases. The human Ark2C is the single known E3 ligase that adopts an alternative, Ub-dependent mechanism for the activation of Ub transfer in the pathway. Its RING domain binds both E2-Ub and free Ub with high affinity, resulting in a catalytic active Ub(R)-RING-E2-Ub(D) complex formation. We examined potential changes in the conformational plasticity of the Ark2C RING domain and its ligands in their complexed form within the ubiquitin pathway through molecular dynamics (MD). Three molecular mechanics force fields compared to previous NMR relaxation studies of RING domain of Arkadia were used for effective and accurate assessment of MDs. Our results suggest the Ark2C Ub-RING docking site has a substantial impact on maintaining the conformational rigidity of E2-E3 assembly, necessary for the E3’s catalytic activity. In the Ub(R)-RING-E2-Ub(D) catalytic complex, the Ub(R) molecule was found to have greater mobility than the other Ub, bound to E2. Furthermore, network-based bioinformatics helped us identify E3 RING ligase candidates which potentially exhibit similar structural modules as Ark2C, along with predicted substrates targeted by the Ub-binding RING Ark2C. Our findings could trigger a further exploration of related unrevealed functions of various other E3 RING ligases. MDPI 2020-10-19 /pmc/articles/PMC7594095/ /pubmed/33086510 http://dx.doi.org/10.3390/molecules25204787 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Mintis, Dimitris G. Chasapi, Anastasia Poulas, Konstantinos Lagoumintzis, George Chasapis, Christos T. Assessing the Direct Binding of Ark-Like E3 RING Ligases to Ubiquitin and Its Implication on Their Protein Interaction Network |
title | Assessing the Direct Binding of Ark-Like E3 RING Ligases to Ubiquitin and Its Implication on Their Protein Interaction Network |
title_full | Assessing the Direct Binding of Ark-Like E3 RING Ligases to Ubiquitin and Its Implication on Their Protein Interaction Network |
title_fullStr | Assessing the Direct Binding of Ark-Like E3 RING Ligases to Ubiquitin and Its Implication on Their Protein Interaction Network |
title_full_unstemmed | Assessing the Direct Binding of Ark-Like E3 RING Ligases to Ubiquitin and Its Implication on Their Protein Interaction Network |
title_short | Assessing the Direct Binding of Ark-Like E3 RING Ligases to Ubiquitin and Its Implication on Their Protein Interaction Network |
title_sort | assessing the direct binding of ark-like e3 ring ligases to ubiquitin and its implication on their protein interaction network |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594095/ https://www.ncbi.nlm.nih.gov/pubmed/33086510 http://dx.doi.org/10.3390/molecules25204787 |
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