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Structural modeling of protein ensembles between E3 RING ligases and SARS-CoV-2: The role of zinc binding domains

BACKGROUND: The ubiquitin system is a modification process with many different cellular functions including immune signaling and antiviral functions. E3 ubiquitin ligases are enzymes that recruit an E2 ubiquitin-conjugating enzyme bound to ubiquitin in order to catalyze the transfer of ubiquitin fro...

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Autores principales: Chasapis, Christos T., Perlepes, Spyros P., Bjørklund, Geir, Peana, Massimiliano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier GmbH. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531365/
https://www.ncbi.nlm.nih.gov/pubmed/36209710
http://dx.doi.org/10.1016/j.jtemb.2022.127089
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author Chasapis, Christos T.
Perlepes, Spyros P.
Bjørklund, Geir
Peana, Massimiliano
author_facet Chasapis, Christos T.
Perlepes, Spyros P.
Bjørklund, Geir
Peana, Massimiliano
author_sort Chasapis, Christos T.
collection PubMed
description BACKGROUND: The ubiquitin system is a modification process with many different cellular functions including immune signaling and antiviral functions. E3 ubiquitin ligases are enzymes that recruit an E2 ubiquitin-conjugating enzyme bound to ubiquitin in order to catalyze the transfer of ubiquitin from the E2 to a protein substrate. The RING E3s, the most abundant type of ubiquitin ligases, are characterized by a zinc (II)-binding domain called RING (Really Interesting New Gene). Viral replication requires modifying and hijacking key cellular pathways within host cells such as cellular ubiquitination. There are well-established examples where a viral proteins bind to RING E3s, redirecting them to degrade otherwise long-lived host proteins or inhibiting E3’s ubiquitination activity. Recently, three binary interactions between SARS-CoV-2 proteins and innate human immune signaling Ε3 RING ligases: NSP15-RNF41, ORF3a-TRIM59 and NSP9-MIB1 have been experimentally established. METHODS: In this work, we have investigated the mode of the previous experimentally supported NSP15-RNF41, ORF3a,-TRIM59 and NSP9-MIB1 binary interactions by in silico methodologies intending to provide structural insights of E3-virus interplay that can help identify potential inhibitors that could block SARS-CoV-2 infection of immune cells. CONCLUSION: In silico methodologies have shown that the above human E3 ligases interact with viral partners through their Zn(II) binding domains. This RING mediated formation of stable SARS-CoV-2-E3 complexes indicates a critical structural role of RING domains in immune system disruption by SARS-CoV-2-infection. DATA AVAILABILITY: The data used to support the findings of this research are included within the article and are labeled with references.
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spelling pubmed-95313652022-10-04 Structural modeling of protein ensembles between E3 RING ligases and SARS-CoV-2: The role of zinc binding domains Chasapis, Christos T. Perlepes, Spyros P. Bjørklund, Geir Peana, Massimiliano J Trace Elem Med Biol Article BACKGROUND: The ubiquitin system is a modification process with many different cellular functions including immune signaling and antiviral functions. E3 ubiquitin ligases are enzymes that recruit an E2 ubiquitin-conjugating enzyme bound to ubiquitin in order to catalyze the transfer of ubiquitin from the E2 to a protein substrate. The RING E3s, the most abundant type of ubiquitin ligases, are characterized by a zinc (II)-binding domain called RING (Really Interesting New Gene). Viral replication requires modifying and hijacking key cellular pathways within host cells such as cellular ubiquitination. There are well-established examples where a viral proteins bind to RING E3s, redirecting them to degrade otherwise long-lived host proteins or inhibiting E3’s ubiquitination activity. Recently, three binary interactions between SARS-CoV-2 proteins and innate human immune signaling Ε3 RING ligases: NSP15-RNF41, ORF3a-TRIM59 and NSP9-MIB1 have been experimentally established. METHODS: In this work, we have investigated the mode of the previous experimentally supported NSP15-RNF41, ORF3a,-TRIM59 and NSP9-MIB1 binary interactions by in silico methodologies intending to provide structural insights of E3-virus interplay that can help identify potential inhibitors that could block SARS-CoV-2 infection of immune cells. CONCLUSION: In silico methodologies have shown that the above human E3 ligases interact with viral partners through their Zn(II) binding domains. This RING mediated formation of stable SARS-CoV-2-E3 complexes indicates a critical structural role of RING domains in immune system disruption by SARS-CoV-2-infection. DATA AVAILABILITY: The data used to support the findings of this research are included within the article and are labeled with references. Elsevier GmbH. 2023-01 2022-10-04 /pmc/articles/PMC9531365/ /pubmed/36209710 http://dx.doi.org/10.1016/j.jtemb.2022.127089 Text en © 2022 Elsevier GmbH. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Chasapis, Christos T.
Perlepes, Spyros P.
Bjørklund, Geir
Peana, Massimiliano
Structural modeling of protein ensembles between E3 RING ligases and SARS-CoV-2: The role of zinc binding domains
title Structural modeling of protein ensembles between E3 RING ligases and SARS-CoV-2: The role of zinc binding domains
title_full Structural modeling of protein ensembles between E3 RING ligases and SARS-CoV-2: The role of zinc binding domains
title_fullStr Structural modeling of protein ensembles between E3 RING ligases and SARS-CoV-2: The role of zinc binding domains
title_full_unstemmed Structural modeling of protein ensembles between E3 RING ligases and SARS-CoV-2: The role of zinc binding domains
title_short Structural modeling of protein ensembles between E3 RING ligases and SARS-CoV-2: The role of zinc binding domains
title_sort structural modeling of protein ensembles between e3 ring ligases and sars-cov-2: the role of zinc binding domains
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531365/
https://www.ncbi.nlm.nih.gov/pubmed/36209710
http://dx.doi.org/10.1016/j.jtemb.2022.127089
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