The zinc proteome of SARS-CoV-2

Abstract

Zinc is an essential element for human health. Among its many functions, zinc(II) modulates the immune response to infections and, at high concentrations or in the presence of ionophores, inhibits the replication of various RNA viruses. Structural biology studies on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) revealed that zinc(II) is the most common metal ion that binds to viral proteins. However, the number of zinc(II)-binding sites identified by experimental methods is far from exhaustive, as metal ions may be lost during protein purification protocols. To better define the zinc(II)-binding proteome of coronavirus, we leveraged the wealth of deposited structural data and state-of-the-art bioinformatics methods. Through this in silico approach, 15 experimental zinc(II) sites were identified and a further 22 were predicted in Spike, open reading frame (ORF)3a/d, ORF8, and several nonstructural proteins, highlighting an essential role of zinc(II) in viral replication. Furthermore, the structural relationships between viral and eukaryotic sites (typically zinc fingers) indicate that SARS-CoV-2 can compete with human proteins for zinc(II) binding. Given the double-edged effect of zinc(II) ions, both essential and toxic to coronavirus, only the complete elucidation of the structural and regulatory zinc(II)-binding sites can guide selective antiviral strategies based on zinc supplementation.

Metal-coding assisted serological multi-omics profiling deciphers the role of selenium in COVID-19 immunity

“…Aer being infected with SARS-CoV-2, we observed an evident decrease of multiple metal(loid)s (Se, Zn, Ca, Mg, K, I, Cr and Mo) in COVID-19 patients, among which some metal(loid)s e.g., Se, Zn, even show signicant variations with disease severity. It is reported that multiple metal ions, e.g., Zn 2+ , 27,28 are critical cofactors of many viral enzymes, proteases and polymerases that aid in viral replication and are required for proper functions of several non-structural proteins in SARS-CoV-2. The disturbance of the metabolism of these metals may result from the competition of essential elements between virus and hosts.…”

“…It is reported that multiple metal ions, e.g. , Zn 2+ , 27,28 are critical cofactors of many viral enzymes, proteases and polymerases that aid in viral replication and are required for proper functions of several non-structural proteins in SARS-CoV-2. The disturbance of the metabolism of these metals may result from the competition of essential elements between virus and hosts.…”

“…For example, Zn 2+ , Fe 2+/3+ and Mn 2+ are required for proper functions of several nonstructural proteins in SARS-CoV-2. [25][26][27][28] Certain nutritional metal ions (e.g. Zn 2+ ) were also reported to exert direct antiviral activity against COVID-19 through inhibition of its replication.…”

Serum Proteome Signatures of Anti-SARS-CoV-2 Vaccinated Healthcare Workers in Greece Associated with Their Prior Infection Status

“…Zinc is a vital element for the proper function of our immune system against infections acting as an immunomodulator and inhibiting viral replication [ 23 ]. Studies have highlighted the role of zinc in COVID-19 as being the main ion that binds to SARS-CoV-2 through several zinc-binding sites recognized through proteomic analysis of the virus [ 24 ]. These studies have evidenced the binary effect of zinc on SARS-CoV-2, as its binding can prove both fundamental for viral reproduction as well as toxic.…”

Structural Bioinformatics and Deep Learning of Metalloproteins: Recent Advances and Applications

“…The latter tool, called MetalS 3 , is available as a web server at (accessed on 5 July 2022) [ 56 ]. As an example, in a recent application we used MetalS 3 to investigate systematically the similarities between the zinc(II)-proteome of SARS-CoV-2 and known metalloprotein structures, uncovering the fact that the large majority of viral MBSs are close to eukaryotic zinc(II) sites [ 57 ].…”