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SARS-CoV2 envelope protein: non-synonymous mutations and its consequences Abstract In the NCBI database, as on June 6, 2020, total number of available complete genome sequences of SARS-CoV2 across the world is 3617. The envelope (E) protein of SARS-CoV2 possesses several non-synonymous mutations over the transmembrane and C-terminus domains in 15 (0.414%) genomes among 3617 SARS-CoV2 genomes, analyzed. More precisely, 10(0.386%) out of 2588 genomes from the USA, 3(0.806%) from Asia, 1 (0.348%) from Europe and 1 (0.274%) from Oceania contained the missense mutations over the E-protein of SARS-CoV2 genomes. The C-terminus motif DLLV has been to DFLV and YLLV in the proteins from QJR88103 (Australia: Victoria) and QKI36831 (China: Guangzhou) respectively, which might affect the binding of this motif with the host protein PALS1. Highlights • In the NCBI database, as on June 6, 2020, total number of available complete genome sequences of SARS-CoV2 across the world is 3617 on which the present study of mutation over the envelope protein is performed. . • The envelope protein of SARS-CoV2 possesses several nonsynonymous mutations over the transmembrane domain and (C)terminus in 15 genomes among 3617 available SARSCoV2 genomes. • The C-terminus motif DLLV has been changed to DFLV and YLLV in the proteins QJR88103 (Australia: Victoria) and QKI36831 (China: Guangzhou) respectively, which might affect the binding of this motif with the host protein PALS1. 1 Introduction The present pandemic situation of the Severe Acute Respiratory Syndrome (COVID-19) is caused by the RNA virus SARS-CoV2 which is characterized by its rapid mutations up to a million times higher than that of their hosts [1]. Several mutations have been detected in various proteins of the SARS-CoV2 over a short period of time, which are recently reported in various articles [[2], [3], [4]]. Genomic variations and evolution enabled the virus to escape host immunity [5,6]. So, such variability would help the scientists towards the drug development [1]. Among various proteins of SARS-CoV2, spike(S), envelope (E), membrane(M) and nucleocapsid (N) are the four structural proteins which help them in assembling and releasing new copies of the virus within human cell [7]. The CoV envelope (E) protein is the smallest among the four structural proteins involved in several aspects of the virus life cycle, such as assembly, budding, envelope formation, and pathogenesis [7]. However, the molecular mechanism involving E-protein in pathogenesis is not yet clearly understood. Notably, this protein interacts with other structural proteins such as membrane(M) and other accessory proteins viz. ORF3a, ORF7a and host cell proteins [8]. Envelope protein of SARS-CoV2 is 76 amino acids long and possesses three important domains viz. (N)-terminus, transmembrane domain (TMD) and (C)-terminus (Fig. 1 ). The (C)-terminal domain of envelope protein in SARS-CoV2 binds to human PALS1, a tight junction-associated protein, which is essential for the establishment and maintenance of epithelial polarity in mammals [9,10]. Fig. 1 Amino acid sequence and domains of the envelope protein of SARS-CoV2 [7]. Red and blue colors are representing hydrophobic and hydrophilic amino acid, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Four mutations including one deletion have been found in the envelope protein of SARS-CoV2 with reference to the SARS-CoV1, a species of coronavirus that also infects humans, bats and certain other mammals. The alignment of the envelope proteins of the SARS-CoV1 and SARS-CoV2 is given in Fig. 2 . Fig. 2 Clustal alignment of the envelope protein of SARS-CoV1 and SARS-CoV2. Mutations in (C)-terminus domain in the E protein protein of SARS-CoV2 are T55S, V56F, E69R (the mutation of an amino acid A1 to an amino acid A2 is denoted by A1pA2 where p denotes location in the reference amino acid sequence).The deletion mutation of G at the 70th position with respect to the reference envelope protein of SARS-CoV1 is also noted. It is reported that the C-terminus domain of the envelope protein contains the motif DLLV which binds to the host cell PALS1 protein to facilitate infection [9,11,12]. In this present study, non-synonymous mutations over the envelope protein of SARS-CoV2 across the available 3617 SARS-CoV2 genomes (as on 6th June 2020), have been found and accordingly their probable consequences are discussed. 2 Methods From the NCBI virus database, all the protein sequences of 3617 SARS-CoV2 genomes were fetched. Then the amino acid sequences of envelope protein of SARS-CoV2 are exported in fasta format using file operations through Matlab. These sequences (fasta formatted) are blasted using Clustal-Omega and found the mismatched and from their mutations and their associated positions were detected [13]. 3 Results Among these virus genomes from 3617 patients; 2588 were from the USA, 372 were from Asia, 287 were from Europe, 365 were from Oceania and 5 were from Africa. Here, we present the non-synonymous mutations of the E-protein protein over the available 3617 SARS-CoV2 genomes (Table 1 ). It is to be noted that 10 (0.386%) out of 2588 genomes from USA, 3 (0.806%) from Asia, 1 (0.348%) from Europe and 1 (0.274%) from Oceania) contained the missense mutations (Table 1) in the envelope proteins of SARS-CoV2 genomes. Changes of the R-group of each amino acid according to the mutations are also presented (Table-1). It is to be noted that the mutation of an amino acid A 1 to an amino acid A 2 is denoted by A 1 pA 2 where p denotes location in the reference amino acid sequence.• In less than 0.5% of the SARS-CoV2 genomes, the E-protein possesses the missense mutations as adumbrated in the Table 1. In TMD and C-terminus domain, there are nine different mutations where the R-group property changes. But only in QHZ00381, for the mutation L37H in the TMD of the envelope protein causes changes in amino acid from hydrophobic to hydrophilic. • TMD was also observed to be conserved over the SARS-CoV1 and COV2 genomes, but the protein sequences of QJA42107 (USA: VA), QJQ84222(USA: KENNER, LA), QHZ00381(South Korea) and QJS53352(Greece: Athens) possess four mutations A36V, L26F, L37H and L39M, respectively, in the TMD of the envelope protein. Change in the R-group property from Hydrophobic to Hydrophilic in the TMD of the envelope protein of the virus from South Korea may affect the ion channel activity of the envelope protein. • The motif ′DLLV′ has been changed to ′DFLV′ and ′YLLV′ in the proteins QJR88103 (Australia: Victoria) and QKI36831 (China: Guangzhou) due to the mutations L73F and D72Y respectively. These mutations having changes in the motif ′DFLV′ may mis-target the PALS1 at Golgi and delaying TJ formation and accordingly may influence replication and/or infectivity of the virus [10]. • In the C-terminus domain of the E-protein of SARS-CoV2 the amino acid S at 68th position changes to the amino acids F and C in the proteins {QKG87268,  QKG88576} from the USA: Massachusetts and QKI36855 from China: Guangzhou respectively. Note that the mutation of the amino acid S to F keeps the R-group property unchanged (i.e. hydrophobic to hydrophilic) while that of the amino acid S to C changes the R-group from Hydrophilic to Hydrophobic. This would possibly make changes in protein functions and interactions. Table 1 Non- synonymous mutation in the E-protein of SARS-CoV2. Protein-ID Geo-location Mutation Domain Change of R-group QJA42107 USA: VA A36V TMDa Hydrophobic to Hydrophobic QJQ84222 USA: KENNER, LA L26F TMD Hydrophobic to Hydrophobic QHZ00381 South Korea L37H TMD Hydrophobic to Hydrophilic QJS53352 Greece: Athens L39M TMD Hydrophobic to Hydrophobic QJR88103 Australia: Victoria L73F C-terminus Hydrophobic to Hydrophobic QKE45838 USA: CA P71L C-terminus Hydrophobic to Hydrophobic QKE45886 USA: CA P71L C-terminus Hydrophobic to Hydrophobic QKE45898 USA: CA P71L C-terminus Hydrophobic to Hydrophobic QKE45910 USA: CA P71L C-terminus Hydrophobic to Hydrophobic QJE38284 USA: CA P71L C-terminus Hydrophobic to Hydrophobic QIU81527 USA: WA P71L C-terminus Hydrophobic to Hydrophobic QKG87268 USA: Massachusetts S68F C-terminus Hydrophobic to Hydrophobic QKG88576 USA: Massachusetts S68F C-terminus Hydrophobic to Hydrophobic QKI36831 China: Guangzhou D72Y C-terminus Hydrophilic to Hydrophobic QKI36855 China: Guangzhou S68C C-terminus Hydrophilic to Hydrophobic a TMD: transmembrane domain. 4 Concluding remarks Among all the proteins present in the novel RNA virus, some accessory proteins such as ORF6, ORF7b, ORF8, ORF10 contain the least number of missense mutation as reported in various studies [[14], [15], [16]]. And same is true for E-protein. We find 15 among 3617 (0.414%) of the SARS-CoV2 genome contains eight different types of mutations in TMD and C-terminus of the envelope protein. Mutated E-protein might affect replication and propagation of the SARS-CoV2 as has been observed in cases of SARS-CoV and MERS-CoV in mouse model [17]. Potential studies have also shown that vaccine against the E-protein mutated viruses can reduce the infectivity in mouse model. Author contributions SH conceived the problem and examined the mutations. SH, PPC, BR analyzed the data and result. SH wrote the initial draft which was checked and edited by all other authors to generate the final version. Declaration of Competing Interest The authors do not have any conflicts of interest to declare.

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