Abstract
More than a decade, overlapping genes in RNA viruses became a subject of research which has explored various effect of gene overlapping on the evolution and function of viral genomes like genome size compaction. Additionally, overlapping regions (OVRs) are also reported to encode elevated degree of protein intrinsic disorder (PID) in unspliced RNA viruses. With the aim to explore the roles of OVRs in HIV-1 pathogenesis, we have carried out an in-depth analysis on the association of gene overlapping with PID in 35 HIV1- M subtypes. Our study reveals an over representation of PID in OVR of HIV-1 genomes. These disordered residues endure several vital, structural features like short linear motifs (SLiMs) and protein phosphorylation (PP) sites which are previously shown to be involved in massive host–virus interaction. Moreover, SLiMs in OVRs are noticed to be more functionally potential as compared to that of non-overlapping region. Although, density of experimentally verified SLiMs, resided in 9 HIV-1 genes, involved in host–virus interaction do not show any bias toward clustering into OVR, tat and rev two important proteins mediates host–pathogen interaction by their experimentally verified SLiMs, which are mostly localized in OVR. Finally, our analysis suggests that the acquisition of SLiMs in OVR is mutually exclusive of the occurrence of disordered residues, while the enrichment of PPs in OVR is solely dependent on PID and not on overlapping coding frames. Thus, OVRs of HIV-1 genomes could be demarcated as potential molecular recognition sites during host–virus interaction.
Highlights
We have found that overlapping regions (OVRs) attributed to the overrepresentation of Short linear motifs (SLiMs) and PPs in Human Immunodeficiency Virus (HIV)-1 genome
Gene overlapping is a common phenomenon in viral genomes and has several important implications and significances in viral evolution (Hughes et al, 2001; Guyader and Ducray, 2002; Pavesi, 2006; Zhao et al, 2007)
In order to do so, we have analyzed the properties of OVR encoded proteins and noticed that they encode a considerable amount of structural disorder as compared to non-overlapping region (NOVR)
Summary
Overlapping regions (OVR) where one DNA sequence codes for multiple proteins with different reading frames, are omnipresent in diverse life forms, for instance, it has been observed in the genomes of acellular obligate parasites like virus (Barrell et al, 1976; Pavesi, 2006; Chirico et al, 2010; Simon-Loriere et al, 2013), prokaryotes including archaea (Saha et al, 2016) and eubacteria (Saha et al, 2016) and subsequently in complex eukaryotes such as human (Veeramachaneni et al, 2004; Makalowska et al, 2007; Sanna et al, 2008). In another study, Rancurel et al (2009) reported that OVRs in unspliced RNA virus genomes encode significant amount of structural disorder. These intrinsically disordered proteins play an essential part in viral proteome as they are typically enriched with Short linear motifs (SLiMs) (Fuxreiter et al, 2007), posttranslational modification sites (PTMs; Gao et al, 2013; Kurotani et al, 2014), and proteolytic cleavage sites (Fan et al, 2014). Our study aims to explore whether OVRs in HIV-1 genome encode intrinsically disordered proteins or not, if yes, how these disordered regions are utilized to successfully invade host cellular machinery
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