Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 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.

PubMed Disclaimer

Conflict of interest statement

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

Figures

ga1
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

Similar articles

See all similar articles

Cited by

References

    1. Shemesh M., Aktepe T.E., Deerain J.M., McAuley J.L., Audsley M.D., David C.T., Purcell D.F.J., Urin V., Hartmann R., Moseley G.W., Mackenzie J.M., Schreiber G., Harari D. SARS-CoV-2 suppresses IFNbeta production mediated by NSP1, 5, 6, 15, ORF6 and ORF7b but does not suppress the effects of added interferon. PLOS Pathog. 2021;17(8) doi: 10.1371/journal.ppat.1009800. - DOI - PMC - PubMed
    1. Lan J., Ge J., Yu J., Shan S., Zhou H., Fan S., Zhang Q., Shi X., Wang Q., Zhang L., Wang X. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020;581(7807):215–220. doi: 10.1038/s41586-020-2180-5. - DOI - PubMed
    1. Lu Q., Liu J., Zhao S., Gomez Castro M.F., Laurent-Rolle M., Dong J., Ran X., Damani-Yokota P., Tang H., Karakousi T., Son J., Kaczmarek M.E., Zhang Z., Yeung S.T., McCune B.T., Chen R.E., Tang F., Ren X., Chen X., Hsu J.C.C., Teplova M., Huang B., Deng H., Long Z., Mudianto T., Jin S., Lin P., Du J., Zang R., Su T.T., Herrera A., Zhou M., Yan R., Cui J., Zhu J., Zhou Q., Wang T., Ma J., Koralov S.B., Aifantis I., Segal L.N., Diamond M.S., Khanna K.M., Stapleford K.A., Cresswell P., Liu Y., Ding S., Xie Q., Wang J. SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2. Immunity. 2021;54(6):1304–1319. doi: 10.1016/j.immuni.2021.05.006. - DOI - PMC - PubMed
    1. Chasapis C.T., Spyroulias G.A. RING finger E(3) ubiquitin ligases: structure and drug discovery. Curr. Pharm. Des. 2009;15(31):3716–3731. doi: 10.2174/138161209789271825. - DOI - PubMed
    1. Chasapis C.T., Loutsidou A.K., Orkoula M.G., Spyroulias G.A. Zinc binding properties of engineered RING finger domain of arkadia E3 ubiquitin ligase. Bioinorg. Chem. Appl. 2010 doi: 10.1155/2010/323152. - DOI - PMC - PubMed