SARS-CoV-2 enzyme Hel

Non-structural protein 13 (nsp13)/ Helicase (Hel)

Function

The multifunctional non-structural protein nsp13, also referred to as helicase, contains 601 amino acids^[1] and is encoded on the ORF1b^[2]. It is part of the superfamily 1B^[3] and highly conserved within all coronaviruses^[4]. Nsp13 is a key enzyme of the viral replication that initiates the first step of the RNA cap synthesis. The capping of the viral RNA is essential to protect it from cellular innate immunity attack, to stabilize it and ensure its translation^[5]. The process of installing the type 1 cap (m7GpppNm-RNA) involves the enzymes nsp13, nsp14, nsp16 and nsp10, with nsp10 acting as an allosteric activator for nsp14 and nsp16, and a still unknown GTase^[4]. Here nsp13 works as an RNA 5’-triphosphatase and hydrolyses the 5’ γ-phosphate of the pppN-RNA as the first step of the capping process^[4].

Another function of the nsp13 is the NTP-dependent unwinding of RNA duplexes with a 5’ to 3’ polarity. This activity is stimulated by interaction with nsp12, the RNA-dependent RNA polymerase (RdRp) ^[3][4].

Additionally, nsp13 might act as a potent interferon antagonist^[6].

Disease

The global COVID-19 pandemic, which started in 2019, is caused by the SARS-CoV-2.

Structure

Compared to the amino acid sequence of SARS-CoV, the SARS-CoV-2 sequence of nsp13 has one amino acid substitution, resulting in a sequence identity of 99.8% and a sequence similarity of 100.0%^[1]. Due to this near perfect match, the nsp13 of SARS-CoV and SARS-CoV-2 share the same structure^[4]. Both show many structural similarities with the eukaryotic Upf1 helicase^[4].

Nsp13 comprises of five domains: The N-terminal Zinc binding domain (ZBD) (amino acids 1-100), the stalk domain (101-150), 1B (151-261), 1A (262-442), and the 2A domain (443-601). The last three have been shown to be responsible for nucleic acid binding and the NTPase activity, while the ZBD and 1A can directly interact with nsp12 to enhance the helicase activity of nsp13. Together they fold in a triangular shape with 1A, 1B and 2A forming the base and the stalk domain and ZBD at the apex^[4]. Nsp13 might form a stable holo-RdRp complex with nsp12, nsp7 and nsp8 by interacting with the nsp8 extensions and the nsp12 thumb domain and may play a role in backtracking^[3].

See also

Coronavirus_Disease 2019 (COVID-19)