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Open AccessArticle

Assessing the Direct Binding of Ark-Like E3 RING Ligases to Ubiquitin and Its Implication on Their Protein Interaction Network

1
Laboratory of Statistical Thermodynamics and Macromolecules, Department of Chemical Engineering, University of Patras & FORTH/ICE-HT, 26504 Patras, Greece
2
Biological Computation & Process Lab, Chemical Process & Energy Resources Institute, Centre for Research & Technology Hellas, 57001 Thessaloniki, Greece
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Laboratory of Molecular Biology and Immunology, Department of Pharmacy, University of Patras, 26504 Patras, Greece
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Institute of Research and Innovation-IRIS, Patras Science Park SA, Stadiou, Platani, Rio, 26504 Patras, Greece
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NMR Center, Instrumental Analysis Laboratory, School of Natural Sciences, University of Patras, 26504 Patras, Greece
6
Institute of Chemical Engineering Sciences, Foundation for Research and Technology, Hellas (FORTH/ICE-HT), 26504 Patras, Greece
*
Authors to whom correspondence should be addressed.
Academic Editors: Antonio Rosato, Francesco Musiani and Claudia Andreini
Molecules 2020, 25(20), 4787; https://doi.org/10.3390/molecules25204787
Received: 9 September 2020 / Revised: 15 October 2020 / Accepted: 16 October 2020 / Published: 19 October 2020
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 UbR-RING-E2-UbD 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 UbR-RING-E2-UbD catalytic complex, the UbR 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. View Full-Text
Keywords: E3 RING ligases; ubiquitin; molecular dynamics; PPI network E3 RING ligases; ubiquitin; molecular dynamics; PPI network
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MDPI and ACS Style

Mintis, D.G.; Chasapi, A.; Poulas, K.; Lagoumintzis, G.; Chasapis, C.T. Assessing the Direct Binding of Ark-Like E3 RING Ligases to Ubiquitin and Its Implication on Their Protein Interaction Network. Molecules 2020, 25, 4787. https://doi.org/10.3390/molecules25204787

AMA Style

Mintis DG, Chasapi A, Poulas K, Lagoumintzis G, Chasapis CT. Assessing the Direct Binding of Ark-Like E3 RING Ligases to Ubiquitin and Its Implication on Their Protein Interaction Network. Molecules. 2020; 25(20):4787. https://doi.org/10.3390/molecules25204787

Chicago/Turabian Style

Mintis, Dimitris G.; Chasapi, Anastasia; Poulas, Konstantinos; Lagoumintzis, George; Chasapis, Christos T. 2020. "Assessing the Direct Binding of Ark-Like E3 RING Ligases to Ubiquitin and Its Implication on Their Protein Interaction Network" Molecules 25, no. 20: 4787. https://doi.org/10.3390/molecules25204787

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