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 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 E3 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 in-dicates 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.

Automated summary

In this study, the mode of interaction between SARS-CoV-2 proteins and human immune signaling E3 RING ligases was investigated using in silico methodologies. The results showed that the viral proteins interact with the human E3 ligases through their Zn(II) binding domains, indicating the critical structural role of RING domains in immune system disruption by SARS-CoV-2 infection.