Amino Acid Patterns Reveal Involvement of Open Reading Frame 4 in HEV Pathogenesis: A Protein with Multiple Functions

Hepatitis E virus (HEV) is a small RNA virus. The unique component open reading frame 4 (ORF4) has been demonstrated to perform crucial functions in the HEV Genotype I (GT I). The amino acid pattern of HEV-ORF4 was systematically examined by computer predictors to explicate its role in viral pathogenesis. Amino acid distribution showed ORF4 was enriched with disorder-promoting residues (Ala, Arg, Pro, Ser, Gly) and a few order-promoting residues (Leu), in combination with structure-breaking resides (Gly and Pro). The ORF4 showed a deficiency in order-promoting residues, like Asn, Phe, Tyr, and Trp. This initial examination revealed a preponderance of disordered regions interpreting ORF4 as proteins consisting of disordered regions, i.e., proteins consisting of disordered regions with structured globular domains). The IDRs (intrinsically disordered regions) as IDPs (intrinsically disordered proteins)/IDPRs (intrinsically disordered protein regions) play a critical role in various regulatory functions of viruses, thus were examined that revealed ORF4 exhibited the characteristics of ORDP (ordered protein), IDPR and IDP. Further, the identified disorder-based protein binding sites revealed the involvement of ORF4 in diverse crucial biological functions, substantiating them as targets of regulation. As ORF4 functions are yet to be completely explored, thus, our data could help in elucidating its functions. Collectively, data from this comprehensive investigation suggest the ORF4 protein’s role in the regulation and pathogenesis of HEV.