The role of intrinsically disordered regions of SARS-CoV-2 Nucleocapsid and Non-structural protein 1 proteins

Getasew Shitaye^1,2Nataliia Ventserova¹Gianluca D'Abrosca³Martina Dragone¹Eunice Wairimu Maina¹Roberto Fattorusso¹Rosa Iacovino¹Luigi Russo¹Carla Isernia^1*Gaetano Malgieri^1*

• ¹Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania Luigi Vanvitelli, Caserta, Italy
• ²Department of Biomedical Sciences, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia, Bahir Dar, Ethiopia
• ³Department of Human Sciences, Link Campus University, Roma, Italy

Virus survival inside the host cell depends on the intricate mechanisms that recruit proteins involved in the arms race. Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) proteome exhibits important levels of structural order. However, some of the SARS-CoV-2 proteins, such as the Nucleocapsid (N) and Non-structural protein 1 (Nsp1), contain a considerably significant amount of intrinsically disordered regions (IDRs) that play indispensable roles in the intra-viral and virus-host interaction. Here, focusing on proteins that contain a relevant percentage of IDRs, we discuss experimental and computational studies sought to support IDRs as a key player in the interplay with ordered domains, the biological role as potential origin for variants of SARS-CoV-2, and their association with virus transmissibility. Furthermore, we also highlight the potential involvement of IDRs in the viral-host protein interaction and host cellular machinery. Thus, shading lights on the dark proteome of the virus and looking for therapeutic approaches beyond the classic structure-function paradigm may contribute to the efforts sparking the quest for therapeutics.