IIT Mandi Study explains C-terminal part of NSP1 Key protein of Covid virus in host cell

A new study by IIT Mandi researchers has unravelled the part of a key protein structure in the Covid-19 virus, that can facilitate in understanding the mode of action and role of the Key protein (in spread and severity of the disease) for the development of antiviral therapeutics.

The findings of the research have been published in the journal ‘Current Research in Virological Science’ in a paper authored by lead researcher Dr. Rajanish Giri, Assistant Professor at School of Basic Sciences and his co-authors Amit Kumar, Ankur Kumar and Prateek Kumar, along with Dr Neha Garg from the Banaras Hindu University.

"Current Covid-19 treatments simply manage symptoms while the body fights off the infection with its immune defence system. There are, as yet, no confirmed antiviral drugs that can stop the virus from replicating. One route to neutralising any virus is to attack its proteins; such an approach holds true for the Covid-19 virus," stated the release.

Elucidating the structure and functions of these proteins is significant for understanding the viral disease and for the development of effective drugs against the virus.

Dr. Rajanish Giri, Assistant Professor of Biotechnology, IIT Mandi explained, “From a conformational or ‘shape’ point of view, several proteins contain ordered and intrinsically disordered regions. These classical conformations are in the proteins in the SARS-CoV-2 virus as well. The structure of non-structural protein 1 (NSP1) is composed of 180 amino acids. The first 1-127 region has been experimentally shown to form an independent structure by Clrak, Green & Petit from University of Alabama. However, there was no experimental proof given by any group on the 131 to 180 amino acid regions of this NSP1 protein, which plays a key role in suppressing the host immune system. With the support of Circular Dichroism spectroscopy and Molecular Dynamics Simulations our group at IIT Mandi has deciphered the conformation of this region in isolation.”

"This virus has sixteen non-structural proteins (NSP1–NSP16), of which, the NSP1 plays a vital role in the pathogenicity (ability to cause disease) of the virus. The NSP1 disrupts the proteins of the host cell and suppresses its immune functions. Its importance can be understood by the fact that it is also called the ‘host shutoff factor’. Particularly Nenad Ban and colleagues have found that if the C-terminal region of NSP1 i.e. 131-180 residues are removed from NSP1 then NSP1 is unable to stop the translation by ribosomes. It is therefore important to understand the molecular mechanisms, biophysical interactions, and chemistry of the interplay of the NSP1 with the host cell," added the release.

“Earlier in 2020, we have shown through bioinformatics studies that NSP1 C-terminal region has intrinsic disorder propensity between 0.4 to 0.5 scales, i.e. very close to borderline of intrinsic disorder prediction. However, without experimental studies, we were not sure that this 131-180 amino acid region is actually an intrinsically disordered protein region. Generally, these regions are unfolded in solution but are folded into particular conformations when binding with specific molecules or partners inside the host cells”, added Dr. Rajanish Giri while explaining the recent developments to his previous research.

"The IIT Mandi team has experimentally studied the structural conformations of SARS-CoV-2 NSP1 under various conditions – in an organic solvent, membrane mimetic environment, and inside liposomes. Using analytical techniques such as circular dichroism spectroscopy, fluorescence spectroscopy, and molecular dynamics simulations, the researchers have shown the dynamic changes in the conformation of the IDR of the NSP1, in response to its surroundings, due to hydrophobic and electrostatic interactions between the protein and the environment," stated the release.

“Our finding provides valuable insight into disorder-order conformation of the NSP1 C-terminal region (residues 131-180) of the SARS-COV2 virus under various environments, which will help in understanding the broader aspect of NSP1 and its interactions with binding partners that are currently unknown”, said Dr. Giri.