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. 2023 Jan:75:127089.
doi: 10.1016/j.jtemb.2022.127089. Epub 2022 Oct 4.

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

Christos T Chasapis  1 , Spyros P Perlepes  2 , Geir Bjørklund  3 , Massimiliano Peana  4
Affiliations

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

Christos T Chasapis et al. J Trace Elem Med Biol. 2023 Jan.

Abstract

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.

Keywords: E3 RING ligases; Haddock; SARS-CoV-2; Zinc binding RING domains.

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Conflict of interest statement

Conflict of interest The authors declare no potential conflicts of interest.

Figures

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Graphical abstract
Fig. 1
Fig. 1
: The cluster of intermolecular contacts at the interface (within the threshold distance of 5.5 Å) for the complexes RNF41-NSP15 (A), TRIM59-ORF3a (B) and MIB1-NSP9 (C).
Fig. 2
Fig. 2
Zn(II) binding domains of TRIM59, RNF41 and MIB1, and their docking interfaces with ORF3a (A), NSP15 (B) and NSP9 (C), respectively.
Fig. 3
Fig. 3
Structural fluctuations (RMSF of Ca atoms per residue) for the polypeptide region (Lys78-Leu138) of RNF41 simulations (blue) and in complex with NSP15 (red) (A); for the RING domain (Cys18-Arg57) of RNF41 simulations (blue) and in complex with NSP15 (red) (B); for the RING domain (Cys10-Arg60) of TRIM59 simulations (blue) and in complex with ORF3a (red) (C); for the RING domain (Cys963-Arg996) of MIB1 simulations (blue) and in complex with NSP9 (red) (D).
Fig. 4
Fig. 4
Intermolecular contacts between (A) TRIM59 and ORF3a (π-π stacking and salt bridges, (B) MIB1 and NSP9 (salt bridges) and (C) RNF41 and NSP15 (salt bridges).
Fig. 5
Fig. 5
Alterations in conformational plasticity of zinc binding domains upon complexation between RNF41-NSP15 (upper panel), TRIM59-ORF3a (medium panel) and MIB1-NSP9 (lower panel).
See this image and copyright information in PMC

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