The prion-like domains of SARS-CoV-2 RBD and ACE2 play important functional roles in virus adhesion and invasion.

The ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a major impact on the global medical system and economy. SARS-CoV-2 is a large enveloped single-stranded RNA virus belonging to the coronaviridae family of the beta coronavirus genus (β-CoV).

study: The prion-like domain of the SARS-CoV-2 spike protein differs between its mutants and allows for altered affinities for ACE2... Image Credit: CROCOTHERY / Shutterstock

Background

In addition to SARS-CoV-2, the other members of the coronavirus family that caused the epidemic and killed many are Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). but, coronavirusColds, human coronavirus OC43 (HCoV-OC43), human coronavirus HKU1 (HCoV-HKU1), etc. are not life-threatening.

All of these viruses mainly infect the epithelial cells of the lungs. However, clinical severity and etiology vary between coronaviruses. For example, pulmonary fibrosis and severe pneumonia are associated with SARS-CoV-2, SARS, and MERS, but HCoV-OC43 and HCoV-HKU1 do not cause these symptoms.

Like other β-CoVs, SARS-CoV-2 encodes four structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins. An important determinant of β-CoV host specificity is the S protein, which is also involved in promoting viral entry into host cells.

The S protein contains two large domains, the N-terminal S1 and the C-terminal S2. The S1 region contains a receptor binding domain (RBD) that detects and binds to the angiotensin converting enzyme 2 (ACE2) receptor in the host cell, which promotes membrane fusion.

Previous studies have shown that S1 has higher genomic variability than S2. That is, the S2 area is highly preserved. Previous studies have shown that SARS-CoV-2 has a higher binding affinity for host ACE2 compared to SARS-CoV.

Since the beginning of the pandemic, many SARS-CoV-2 variants have emerged due to genomic mutations. Some SARS-CoV-2 mutants show higher infection rates and pathogenicity, and show the ability to evade immune responses elicited by immunization or spontaneous infection. These variants are classified by the World Health Organization into variants of concern (VOCs) and variants of interest (VOIs).

The prion-like domain (PrD) is highly associated with the interaction of the virus with the host cell. The molecular mechanism behind prion formation is unclear, but researchers have found that prion formation is driven by the presence of asparagine (Q) and glutamine (N) -rich regions and the hydrophobicity characterized by net sequence charge. I found that it would be done. Several PrD prediction algorithms are available, including prion-like amino acid composition (PLAAC) analysis. This algorithm allows analysis of PrD based on the Hidden Markov Model (HMM). To date, there have been few studies related to the prionogen properties of SARS-CoV-2.

New research

Scientists have recently detected and analyzed the virus PrD in the S protein of SARS-CoV-2. This is a new regulator of virion assembly. They also compared them to other human pathogenic β-CoV PrDs.The study is published at Microorganisms.. Researchers have also found S-proteins of SARS-CoV-2 variants such as B.1.617.2 (delta), B.1.1.529 (omicron), B.1.1.7 (alpha), and B.1.351 (beta). PrD in was determined), P.1 (gamma), B.1.427 (epsilon), B.1.617.1 (kappa), P.2 (zeta).

The results of this study are consistent with previous studies analyzing the pathological function of human prions (eg, Alzheimer’s disease and Parkinson’s disease, and diabetes). Scientists say that misfolding of proteins plays an important role in both prokaryotes and eukaryotes. In the current study, researchers used a high threshold ratio of PLAAC scores to identify proteins and used only proteins with high probable prionogen properties. They observed that SARS-CoV-2 is the only coronavirus that contains PrD in the RBD of the S protein, even though different β-CoV members contain PrD in the S protein.

Scientists have discovered specific amino acids that enable the prionogenicity of SARS-CoV-2 RBD that interacts within ACE2: Q474, N481, Q493, Q498, and N501. Previous studies investigated atomic interactions between SARS-CoV-2 and ACE2 and detected several prion-like segments showing pairwise interactions within natural denaturation. The authors stated that PrD is only present in the SARS-CoV-2 RBD, so their presence should benefit the virus.

Current studies provide evidence of this concept and show that the presence of PrD in the SARS-CoV-2 RBD enhances the affinity of the virus for binding to the host’s ACE2 receptor. Scientists also show that of all SARS-CoV-2 mutants studied, the highest log-likelihood ratio score was observed with the SARS-CoV-2 delta mutant S protein. did. This discovery is important because delta variants show high transmission rates. In addition, this variant is associated with higher mortality and hospitalization.

Conclusion

The authors stated that the current study is the most complete assessment of PrD in the S protein of the SARS-CoV-2 mutant. However, more analysis related to the PrD-containing protein of SARS-CoV-2 is needed to better understand COVID-19 infection. This study provided new awareness of pathophysiology and new targets that could be used to develop effective COVID-19 therapeutics and vaccines.