Revealing highly conserved regions in the E6 protein among distinct human papillomavirus types using comparative analysis of multiple sequence alignments

Abstract

Several epidemiological and molecular studies have confirmed that cervical infection by certain human papillomaviruses (HPV) types is a precursor of the genesis of cervical neoplasia (Gravitt, 2011;Guzmán-Olea et al., 2012). It is yet well elucidated that high risk genotypes lead to the development of cervical cancer and are also associated with other mucosal anogenital, head and neck tumors. The HPV genome is approximately 8 kb in length and is divided into three regions, the non-coding long control region (LCR, ~1 kb), and the protein coding early (E, ~4 kb) and late (L, ~3 kb) regions (Ganguly and Parihar, 2009). The viral genome encodes six early (E1, E2, E4, E5, E6 and E7) and two late (L1 and L2) proteins. HPV E6 and E7 genes encode oncoproteins that cause transformation of the host cell, whose action is involved in maintenance of the HPV genome extrachromosomally. Since HPV immortalisation of keratinocytes in vitro has been identified as an important step in tumor progression in vivo, some studies have provided strong experimental supports for the hypothesis that the maintenance and expression of E6 and E7 proteins observed in human cervical carcinomas has pathologic significance (Hawley-Nelson et al., 1989;Ganguly and Parihar, 2009). The E6 protein in high risk HPV genotypes has been reported to prevent apoptosis by a p53-independent mechanism which involves inhibition of bax gene expression and degradation of Bax protein in human keratinocytes, resulting in inhibition of apoptosis and therefore cells accumulate mutations in their DNA (Magal et al., 2005). Recently, Liu et al. (2009) have suggested that the E6 protein mediates telomerase activation by a posttranscriptional mechanism, exerting potential effects on the direct modulation of cell telomerase/telomere function, and triggering a crucial role in both neoplasia and virus replication.Over the last decades, computational biology tools have opened new insights concerning the characterisation and conservation of biological molecule sequences among distinct viral genomes. Using multiple sequence alignments, the purpose of the present study was to perform comparative analysis of E6 protein segments between high and low risk HPV genotypes. For these analyses, E6 protein segments present in HPV 16 and 18 (high risk and virulent HPV types) and in HPV11 and 06A (low risk and non-virulent HPV types) were selected (Ganguly and Parihar, 2009). Initially, amino acid sequences of E6 protein from these four genotypes were searched using the computational algorithm UniProtKB/Swiss-Prot that provides a high quality annotated and non-redundant protein sequence database (Lesk, 2002;Jungo et al., 2012). Such a search resulted in the identification of amino acid sequences corresponding to E6 protein previously sequenced and deposited in this database with access numbers: P03126 for HPV16, P06463 for HPV18, P04019 for HPV11 and Q84291 for HPV06A.The multiple alignments of the amino acid residues in the E6 viral protein among distinct HPV genotypes were generated using ...

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