Two short low complexity regions (LCRs) are hallmark sequences of the Delta SARS-CoV-2 variant spike protein

Arturo Becerra,Antonio Lazcano,Israel Muñoz-Velasco,José Alberto Campillo-Balderas,Ricardo Hernández-Morales,Abelardo Aguilar-Cámara,Alberto Vázquez-Salazar,Rodrigo Jácome,Wolfgang Cottom-Salas,Adrián Cruz-González

doi:10.1038/s41598-022-04976-8

Abstract

Low complexity regions (LCRs) are protein sequences formed by a set of compositionally biased residues. LCRs are extremely abundant in cellular proteins and have also been reported in viruses, where they may partake in evasion of the host immune system. Analyses of 28,231 SARS-CoV-2 whole proteomes and of 261,051 spike protein sequences revealed the presence of four extremely conserved LCRs in the spike protein of several SARS-CoV-2 variants. With the exception of Iota, where it is absent, the Spike LCR-1 is present in the signal peptide of 80.57% of the Delta variant sequences, and in other variants of concern and interest. The Spike LCR-2 is highly prevalent (79.87%) in Iota. Two distinctive LCRs are present in the Delta spike protein. The Delta Spike LCR-3 is present in 99.19% of the analyzed sequences, and the Delta Spike LCR-4 in 98.3% of the same set of proteins. These two LCRs are located in the furin cleavage site and HR1 domain, respectively, and may be considered hallmark traits of the Delta variant. The presence of the medically-important point mutations P681R and D950N in these LCRs, combined with the ubiquity of these regions in the highly contagious Delta variant opens the possibility that they may play a role in its rapid spread.

Highlights

Protein segments that exhibit a bias in their composition can be formed by (a) a small number of different amino acids, in which case they are called low complexity regions (LCRs); or (b) homopolymers or homorepeats, if they consist of a long repetition of a single amino a cid[1,2]
Our results demonstrate that these two conserved (98–99%) short LCRs are hallmark sequences of the highly transmissible Delta SARS-CoV-2 variant, which suggest that they might play a significant role in the viral adaptation and rapid spread of this variants of concern (VOC)
In this work we have named each LCR according to the following rules: the first word of the name corresponds to the protein in which the LCR is located, and the number corresponds to its position in each of the SARS-CoV-2 proteins (Table S3)

Summary

Introduction

Protein segments that exhibit a bias in their composition can be formed by (a) a small number of different amino acids, in which case they are called low complexity regions (LCRs); or (b) homopolymers or homorepeats, if they consist of a long repetition of a single amino a cid[1,2]. LCRs are scattered throughout the SARS-CoV-2 proteome, and are more prevalent in the non-structural protein 3, spike protein, and the nucleocapsid protein, where they may simultaneously enhance immune evasion and induce a strong immunogenic r esponse[11]. They are conspicuously absent in several proteins of the replicationtranscription complex (RdRp, helicase, and NSP14 exonuclease), and in the NSP1, 3CL protease, NSP9-11, NSP15, ORF3a, membrane (M) protein, ORF6, ORF8 and ORF10 p roteins[11]. Our results demonstrate that these two conserved (98–99%) short LCRs are hallmark sequences of the highly transmissible Delta SARS-CoV-2 variant, which suggest that they might play a significant role in the viral adaptation and rapid spread of this VOC

Methods

Results

Conclusion