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Abstract
Currently, the world is struggling with the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Prion-like domains are critical for virulence and the development of therapeutic targets; however, the prion- like domains in the SARS-CoV-2 proteome have not been analyzed. In this in silico study, using the PLAAC algorithm, we identified the presence of prion-like domains in the SARS-CoV-2 spike protein. Compared with other viruses, a striking difference was observed in the distribution of prion-like domains in the spike protein, since SARS-CoV-2 was the only coronavirus with a prion- like domain found in the receptor-binding domain of the S1 region of the spike protein. The presence and unique distribution of prion-like domains in the SARS-CoV-2 receptor-binding domains of the spike protein is particularly interesting, since although the SARS-CoV-2 and SARS-CoV S proteins share the same host cell receptor, angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 demonstrates a 10- to 20-fold higher affinity for ACE2. Finally, we identified prion-like domains in the α1 helix of the ACE2 receptor that interact with the viral receptor-binding domain of SARS-CoV-2. Taken together, the present findings indicate that the identified PrDs in the SARS-CoV-2 receptor-binding domain (RBD) and ACE2 region that interact with RBD have important functional roles in viral adhesion and entry.
Introduction The world is struggling with the pandemic caused by a novel coronavirus (now named severe acute respiratory syndrome-2 or SARS-CoV-2, causing the disease COVID-19) that has expanded from Wuhan throughout China (1). By March 30, 2020, the virus had caused over 775,000 confirmed cases worldwide and contributed to over 37,000 deaths (https://www.worldometers.info/coronavirus/). SARS-CoV-2 is a new member of the Betacoronavirus (β-CoV) genus of large, enveloped single- stranded RNA viruses (2). This genus not only includes viruses that cause deadly human infections such as severe acute respiratory syndrome (SARS) and Middle East respiratory |
syndrome (MERS), but also encompasses viruses that cause non-life-threatening common colds, including human coronavirus OC43 (HCoV-OC43) and human coronavirus HKU1 (HCoV-HKU1) (3). Although these viruses predominantly infect lung epithelial cells, the clinical severity and pathogenesis of the infections they cause varies between different coronaviruses (4). While severe pneumonia and pulmonary fibrosis are fundamental to the pathogenesis of COVID-19, SARS, and MERS, these symptoms are not typical of infections caused by HCoV-OC43 and HCoV-HKU1 (5,6). |
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 29 March 2020 doi:10.20944/preprints202003.0422.v1 |
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Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 29 March 2020 doi:10.20944/preprints202003.0422.v1 |
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Discussion
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Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 29 March 2020 doi:10.20944/preprints202003.0422.v1 |
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Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 29 March 2020 doi:10.20944/preprints202003.0422.v1 |
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Domain Prion-like domain AA position RBD SARS-CoV HR1 MERS-CoV NA HCoV-OC43 NA S protein 473-510 900-910 Non-detectable Non-detectable SARS-CoV-2 |
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 29 March 2020 doi:10.20944/preprints202003.0422.v1 |
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The RBD of the SARS-CoV-2 spike protein was aligned against the closest related human βCoV, SARS-CoV. The PrDs of SARS-CoV-2 are red. Different residues are denoted by an “*” beneath the consensus position. The amino acids asparagine (Q) and glutamine (N) in the PrDs of the SARS-CoV-2 RBD that differ from the amino acids in the SARS-CoV RBD are denoted by red “**” beneath the consensus position. Amino acids of the SARS-CoV-2 RBD that bind to ACE2 are marked with red boxes. RBD - Receptor binding domain. |
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 29 March 2020 doi:10.20944/preprints202003.0422.v1 |
Figure 2. Interactions between amino acids of PrDs and non-prion-like regions of SARS- CoV-2 RBD and ACE2. (A) The amino acids Q498 and T500 from the PrD of the SARS-CoV2 RBD interact with Y41 and Q42 within the PrD of ACE2, while Q474, F486 and N501 from the PrD of the SARS-CoV-2 RBD bind to Q24, M82 and K343 from the non-PrD of ACE2. K417 and Y453 were the only amino acids of the SARS-CoV-2 RBD that were outside the viral PrD and bound to ACE2. (B to D) Detailed analysis of the interface between the SARS-CoV-2 RBD and ACE2. The structure of the RBD-ACE2 complex was established based on the data from PDB ID: 6VW1 and visualized using the YASARA software (http://www.yasara.com). The ACE2 and RBD molecules are stained green and blue respectively. Amino acids within the PrD of the RBD that interact with amino acid residues of ACE2 are stained purple, while those in the PrDs of ACE2 that interact with amino acid residues of the RBD are stained green; the interactions are indicated by red, dashed lines. Amino acids within the non-PrD of the RBD that interacts with amino acid residues of ACE2 are yellow, while those in the non-PrDs of ACE2 that interact with amino acid residues of the RBD are orange, and these interactions are indicated by a black dashed line. |
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 29 March 2020 doi:10.20944/preprints202003.0422.v1 |
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Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 29 March 2020 doi:10.20944/preprints202003.0422.v1 |
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Author Contributions Competing interests GT and VT designed the experiments. GT performed the experiments and supervised data analysis. VT and GT analyzed the data and wrote the manuscript.
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