Function
The non-structural protein nsp1, also referred to as leader protein, host translation inhibitor or host shutoff factor, binds to the 40S ribosomal subunit and the 80S ribosome[1]. It contains 180 amino acids[2], is encoded on the ORF1a[3] and is expressed by all betacoronaviruses[4].
By binding to the mRNA channel of the 40S ribosomal subunit, nsp1 shuts down the host protein production. A result is the suppression of a large part of the innate immune system that depends on the translation of antiviral defense factors, like interferons (IFN), other proinflammatory cytokines and antiviral IFN-stimulated genes[5].
Additionally, binding of nsp1 of SARS-CoV to the 40S ribosomal subunit induces the endonucleolytic cleavage of only the host mRNA to suppress the expression of host genes[6].
Disease
The global COVID-19 pandemic, which started in 2019, is caused by the SARS-CoV-2.
Structure
The 3D structure of Nsp1[7][8] consists of a N-terminal domain, a C-terminal domain, and a 20-amino acid long unstructured linker, which flexibly connects the two[1]. The C-terminal domain contains the two α-helices (α1: 154-160, α2: 166-179) and a short loop, which holds the conserved KH-motif (K164 and H165)[5].
The C-terminal domain is known to bind inside the mRNA entry channel of the 40S ribosomal subunit. There its α-helix α1 interacts with the ribosomal proteins uS3 and uS5 of 40S, the KH motif with the rRNA helix h18, and α2 with h18 and uS5. Through hydrophobic interactions both α-helices stabilize each other. The surface charge as well as the shape of the C-terminal domain match with the nsp1 interacting parts of 40S, and overlap the mRNA path[5]. While the C-terminal domain is bound to the 40S mRNA channel, the N-terminal domain can move within a ~60 Å radius from its connection to the C-terminal domain[1].
To maintain the translation of the viral mRNA, the virus has to circumvent the translational blockage, which is induced by the binding of nsp1 to the 40S mRNA channel[1]. How this is accomplished is a matter of debate.
One suggested way is by using the interaction of the N-terminal domain and the 5’ untranslated region (5’ UTR) of the SARS-CoV-2 mRNA[9]. This 5’ UTR is shown to promote translation initiation and to have a complex secondary structure that is conserved among most coronaviruses[1]. As the lengthening of the linker in nsp1 was shown to result in a reduced ability of escaping the translational inhibition, the incompatibility of the simultaneous interaction with 40S and the viral 5’ UTR is suggested to be of steric nature[9]
Another proposal is that the level of nsp1 blocked ribosomes is kept so high, that the remaining unblocked ones will translate the 5’UTR containing viral mRNA with higher efficiency than the cellular mRNA[1].
Variations
Compared to the amino acid sequence of SARS-CoV, the SARS-CoV-2 sequence of nsp1 has 28 amino acid substitutions, resulting in a sequence identity of 84.4% and a sequence similarity of 93.3%[2].
Relevance
Nsp1 is a probably major virulence factor and might therefore be an interesting drug target in association with drugs targeting other parts of the virus[4].
See also
Coronavirus_Disease 2019 (COVID-19)
SARS-CoV-2_virus_proteins
COVID-19 AlphaFold2 Models
