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Role of ORF4 in Hepatitis E virus regulation: analysis of intrinsically disordered regions

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Abstract

Hepatitis E virus (HEV) is one of the causative agents of liver infections. The essential open reading frame 4 (ORF4) encoded protein role in HEV regulation remains undetermined. Intrinsically disordered protein regions (IDPRs)/intrinsically disordered protein (IDPs) in viral proteomes are linked with virus’s pathogenicity and infectivity. Therefore, in the present study, we have examined the unstructured/disordered regions of ORF4 proteins by analyzing the prevalence of intrinsic disorder. The intrinsic disorder propensity analysis of ORF4 proteins revealed JN167538 (Rat) as a structured protein, LC057248 (HEV) and LC177791 (Ferret) as moderately disordered proteins and KU168733 (Human) as a highly disordered protein, categorizing them as ORDP, IDPRs and IDR, respectively. All the ORF4 proteins consisted of molecular recognition features (MoRFs), i.e., intrinsic disorder-based protein–protein interaction (PPI) sites used by proteins to interact with specific partners, in addition to several nucleotide-binding sites. As IDPR and IDP, in conjunction with molecular recognition (PPI, RNA binding and DNA binding), our results signified the ORF4 protein’s interactions with the host membranes and further viral infection. In particular, as IDP, the ORF4 protein (Human) could possibly contribute to viral replication through PPIs. The presence of various disordered-based phosphorylation sites further signified the role of ORF4 proteins in various biological processes, such as post-translational modifications (/PTMs). Furthermore, structure-based analyses of ORF4 proteins revealed it as a multifunctional-associated protein, due to its involvement in various binding and catalytic activities. Collectively, data from this comprehensive investigation suggested ORF4 protein’s role in regulation and pathogenesis of HEV.

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Abbreviations

HEV:

Hepatitis E virus

IDPs:

Intrinsically disordered proteins

IDPRs:

Intrinsically disordered protein regions

MoRFs:

Molecular recognition features

PONDR:

Predictor of natural disordered regions

PPRInt:

Prediction of protein–RNA interaction

PPID:

Predicted percentage of intrinsic disorder

PTM:

Post-translational modification

ORF4:

Open reading frame 4

References

  • Alves C, Cheng H, Roder H, Taylor J (2010) Intrinsic disorder and oligomerization of the hepatitis delta virus antigen. Virology 407(2):333–340

    CAS  PubMed  Google Scholar 

  • Ansari IH, Nanda SK, Durgapal H, Agrawal S, Mohanty SK, Gupta D, Jameel S, Panda SK (2000) Cloning, sequencing, and expression of the hepatitis E virus (HEV) nonstructural open reading frame 1 (ORF1). J Med Virol 60(3):275–283

    CAS  PubMed  Google Scholar 

  • Best SM, Morris KL, Shannon JG, Robertson SJ, Mitzel DN, Park GS, Boer E, Wolfinbarger JB, Bloom ME (2005) Inhibition of interferon-stimulated JAK-STAT signaling by a tick-borne flavivirus and identification of NS5 as an interferon antagonist. J Virol 79(20):12828–12839

    CAS  PubMed  PubMed Central  Google Scholar 

  • Betts MJ, Russell RB (2003) Amino acid properties and consequences of substitutions. Bioinform Genet 317(289):10–12

    Google Scholar 

  • Bhatnagar G, Sharma S, Kumar A, Prasad S, Agarwal S, Kar P (2016) Reduced glutathione in hepatitis E infection and pregnancy outcome. J Obstet Gynaecol Res 42(7):789–795

    CAS  PubMed  Google Scholar 

  • Bhattacharya D, Mayuri BSM, Perera R, Kuhn RJ, Striker R (2009) Protein Kinase G phosphorylates mosquito-borne flavivirus NS5. J Virol 83(18):9195–9205

    CAS  PubMed  PubMed Central  Google Scholar 

  • Boccia D, Guthmann JP, Klovstad H, Hamid N, Tatay M, Ciglenecki I, Nizou JY, Nicand E, Guerin PJ (2006) High mortality associated with an outbreak of hepatitis E among displaced persons in Darfur. Sudan Clin Infect Dis 42(12):1679–1684

    PubMed  Google Scholar 

  • Campen A, Williams RM, Brown CJ, Meng J, Uversky VN, Dunker AK (2008a) TOP-IDP-scale: a new amino acid scale measuring propensity for intrinsic disorder. Protein Pept Lett 15:956–963

    CAS  PubMed  PubMed Central  Google Scholar 

  • Campen A, Williams RM, Brown CJ, Meng J, Uversky VN, Dunker AK (2008b) TOP-IDP-scale: a new amino acid scale measuring propensity for intrinsic disorder. Protein Pept Lett 15(9):956–963

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chandra V, Taneja S, Kalia M, Jameel S (2008) Molecular biology and pathogenesis of hepatitis E virus. J Biosci 33(4):451–464

    CAS  PubMed  Google Scholar 

  • Collins MO, Yu L, Campuzano I, Grant SG, Choudhary JS (2008) Phosphoproteomic analysis of the mouse brain cytosol reveals a predominance of protein phosphorylation in regions of intrinsic sequence disorder. Mol Cell Proteom 7(7):1331–1348

    CAS  Google Scholar 

  • Dafforn TR, Smith CJ (2004) Natively unfolded domains in endocytosis: hooks, lines and linkers. EMBO Rep 5(11):1046–1052

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dé I, Fata-Hartley C, Sawicki SG, Sawicki DL (2003) Functional analysis of nsP3 phosphoprotein mutants of Sindbis virus. J Virol 77(24):13106–13116

    PubMed  PubMed Central  Google Scholar 

  • De Chassey B, Navratil V, Tafforeau L (2008) Hepatitis C virus infection protein network. Mol Syst Biol 4(1):230

    PubMed  PubMed Central  Google Scholar 

  • Denning DP, Rexach MF (2007) Rapid Evolution Exposes the Boundaries of Domain Structure and Function in Natively Unfolded FG Nucleoporins* S. Mol Cell Proteom 6(2):272–282

    CAS  Google Scholar 

  • Diella F, Haslam N, Chica C, Budd A, Michael S, Brown NP, Travé G, Gibson TJ (2008) Understanding eukaryotic linear motifs and their role in cell signaling and regulation. J Front Biosci 13(6580):603

    Google Scholar 

  • Ding Q, Heller B, Capuccino JM, Song B, Nimgaonkar I, Hrebikova G, Contreras JE, Ploss A (2017) Hepatitis E virus ORF3 is a functional ion channel required for release of infectious particles. Proc Natl Acad Sci USA 114(5):1147–1152

    CAS  PubMed  PubMed Central  Google Scholar 

  • Disfani FM, Hsu W-L, Mizianty MJ et al (2012) MoRFpred, a computational tool for sequence-based prediction and characterization of short disorder-to-order transitioning binding regions in proteins. Bioinformatics 28(12):i75–i83

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dosztanyi Z, Chen J, Dunker K, Simon I, Tompa P (2006) Disorder and sequence repeats in hub proteins and their implications for network evolution. J Proteome Res 5(11):2985–2995

    CAS  PubMed  Google Scholar 

  • Dunker AK, Obradovic Z (2001) The protein trinity—linking function and disorder. Nat Biotechnol 19:805–806

    CAS  PubMed  Google Scholar 

  • Dunker AK, Garner E, Guilliot S, Romero P, Albrecht K, Hart J, Obradovic Z, Kissinger C, Villafranca JE (1998) Protein disorder and the evolution of molecular recognition: theory, predictions and observations. Pac Symp Biocomput 1998:473–484

    Google Scholar 

  • Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P, Oh JS, Oldfield CJ, Campen AM, Ratliff CM, Hipps KW, Aussio J, Nissen MS, Reeves R, Kang C, Kissinger CR, Bailey RW, Griswold MD, Chiu W, Garner EC, Obradovic Z (2001a) Intrinsically disordered protein. J Mol Graph Model 19:26–59

    CAS  PubMed  Google Scholar 

  • Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P, Oh JS, Oldfield CJ, Campen AM, Ratliff CM, Hipps KW, Ausio J (2001b) Intrinsically disordered protein. J Mol Graph Model 19:26–59

    CAS  PubMed  Google Scholar 

  • Dunker AK, Lawson JD, Brown CJ (2001c) Intrinsically disordered protein. J Mol Graph Model 3263:26–59

    Google Scholar 

  • Dunker AK, Brown CJ, Lawson JD, Iakoucheva LM, Obradovic Z (2002a) Intrinsic disorder and protein function. Biochemistry 41:6573–6582

    CAS  PubMed  Google Scholar 

  • Dunker AK, Brown CJ, Obradovic Z (2002b) Identification and functions of usefully disordered proteins. Adv Protein Chem 62:25–49

    CAS  PubMed  Google Scholar 

  • Dunker AK, Oldfield CJ, Meng J, Romero P, Yang JY, Chen JW, Vacic V, Obradovic Z, Uversky VN (2008) The unfoldomics decade: an update on intrinsically disordered proteins. BMC Genom 9(2):1–26

    Google Scholar 

  • Dyson HJ, Wright PE (1998) Equilibrium NMR studies of unfolded and partially folded proteins. Nat Struct Biol 5(7):499–503

    CAS  PubMed  Google Scholar 

  • Dyson HJ, Wright PE (2002) Coupling of folding and binding for unstructured proteins. Curr Opin Struct Biol 12:54–60

    CAS  PubMed  Google Scholar 

  • Dyson HJ, Wright PE (2005) Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol 6:197–208

    CAS  PubMed  Google Scholar 

  • Edwards YJ, Lobley AE, Pentony MM, Jones DT (2009) Insights into the regulation of intrinsically disordered proteins in the human proteome by analyzing sequence and gene expression data. Genome Biol 10(5):1–8

    Google Scholar 

  • Erdős G, Dosztányi Z (2020) Analyzing protein disorder with IUPred2A. Curr Protoc Bioinform 70(1):e99

    Google Scholar 

  • Espinoza-Fonseca LM (2009) Thermodynamic aspects of coupled binding and folding of an intrinsically disordered protein: a computational alanine scanning study. Biochemistry 48(48):11332–11334

    CAS  PubMed  Google Scholar 

  • Fischer E (1894) Einfluss der configuration auf die wirkung der enzyme. Ber Dt Chem Ges 27:2985–2993

    CAS  Google Scholar 

  • Forwood JK, Brooks A, Briggs LJ, Xiao CY, Jans DA, Vasudevan SG (1999) The 37-amino-acid interdomain of Dengue Virus NS5 Protein Contains a Functional NLS and Inhibitory CK2 Site. Biochem Biophys Res Commun 257(3):731–737

    CAS  PubMed  Google Scholar 

  • Foster TL, Belyaeva T, Stonehouse NJ, Pearson AR, Harris M (2010) All three domains of the hepatitis C virus nonstructural NS5A protein contribute to RNA binding. J Virol 84:9267–9277

    CAS  PubMed  PubMed Central  Google Scholar 

  • Foy NJ, Akhrymuk M, Akhrymuk I, Atasheva S, Bopda-Waffo A, Frolov I, Frolova EI (2013) Hypervariable domains of nsP3 proteins of New World and Old World alphaviruses mediate formation of distinct, virus-specific protein complexes. J Virol 87(4):1997–2010

    CAS  PubMed  PubMed Central  Google Scholar 

  • Galea CA, Wang Y, Sivakolundu SG, Kriwacki RW (2008) Regulation of cell division by intrinsically unstructured proteins: intrinsic flexibility, modularity, and signaling conduits. Biochemistry 47(29):7598–7609

    CAS  PubMed  Google Scholar 

  • Garner E, Cannon P, Romero P, Obradovic Z, Dunker AK (1998) Predicting disordered regions from amino acid sequence: common themes despite differing structural characterization. Genome Inform Ser Workshop Genome Inform 9:201–213

    CAS  PubMed  Google Scholar 

  • Gerard FCA, Ribeiro EdA, Leyrat C (2009) Modular organization of rabies virus phosphoprotein. J Mol Biol 388:978–996

    CAS  PubMed  Google Scholar 

  • Gianni S, Dogan J, Jemth P (2016) Coupled binding and folding of intrinsically disordered proteins: what can we learn from kinetics? Curr Opin Struct Biol 36:18–24

    CAS  PubMed  Google Scholar 

  • Giri R, Kumar D, Sharma N, Uversky VN (2016) Intrinsically disordered side of the Zika virus proteome. Front Cell Infect Microbiol 6:144

    PubMed  PubMed Central  Google Scholar 

  • Grainger L, Cicchini L, Rak M, Petrucelli A, Fitzgerald KD, Semler BL, Goodrum F (2010) Stress- inducible alternative translation initiation of human cytomegalovirus latency protein pUL138. J Virol 84(18):9472–9486

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gsponer J, Futschik ME, Teichmann SA, Babu MM (2008) Tight regulation of unstructured proteins: from transcript synthesis to protein degradation. Science 322:1365–1368

    CAS  PubMed  PubMed Central  Google Scholar 

  • Habchi J, Longhi S (2012) Structural disorder within paramyxovirus nucleoproteins and phosphoproteins. Mol Biosyst 8:69–81

    CAS  PubMed  Google Scholar 

  • He M, Wang M, Huang Y, Peng W, Zheng Z, Xia N, Xu J, Tian D (2016) The ORF3 protein of genotype 1 hepatitis E virus suppresses TLR3-induced NF-κB signaling via TRADD and RIP1. Sci Rep 6(1):1–13

    Google Scholar 

  • Holt LJ, Tuch BB, Villén J, Johnson AD, Gygi SP, Morgan DO (2009) Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution. Science 325(5948):1682–1686

    CAS  PubMed  PubMed Central  Google Scholar 

  • Iakoucheva LM, Radivojac P, Brown CJ. Oconnor TR, Sikes JG, Obradovic Z, Dunker AK (2004) Nucleic Acids Res 32:1037–1049

  • Iwasaki M, Takeda M, Shirogane Y, Nakatsu Y, Nakamura T, Yanagi Y (2009) The matrix protein of measles virus regulates viral RNA synthesis and assembly by interacting with the nucleocapsid protein. J Virol 83:10374–10383

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jones DT, Cozzetto D (2015) DISOPRED3: precise disordered region predictions with annotated protein-binding activity. Bioinformatics 31(6):857–863

    CAS  PubMed  Google Scholar 

  • Joseph AP, Srinivasan N, de Brevern AG (2012) Cis-trans peptide variations instructurally similar proteins. Amino Acids 43:1369–1381

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kalhan SC, Hanson RW (2012) Resurgence of serine: an often neglected but indispensable amino acid. J Biol Chem 287(24):19786–19791

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kamar N, Selves J, Mansuy JM, Ouezzani L, Péron JM, Guitard J, Cointault O, Esposito L, Abravanel F, Danjoux M, Durand D (2008) Hepatitis E virus and chronic hepatitis in organ-transplant recipients. N Engl J Med 358(8):811–817

    CAS  PubMed  Google Scholar 

  • Kamar N, Izopet J, Pavio N, Aggarwal R, Labrique A, Wedemeyer H, Dalton HR (2017) Hepatitis E virus infection. Nat Rev Dis Primers 3(1):1–6

    Google Scholar 

  • Kapoor M, Zhang L, Ramachandra M, Kusukawa J, Ebner KE, Padmanabhan R (1995) Association between NS3 and NS5 proteins of dengue virus Type 2 in the Putative RNA replicase is linked to differential phosphorylation of NS5. J Biol Chem 270(32):19100–19106

    CAS  PubMed  Google Scholar 

  • Karlin D, Longhi S, Receveur V, Canard B (2002) The n-terminal domain of the phosphoprotein of morbilliviruses belongs to the natively unfolded class of proteins. Virology 296:251–262

    CAS  PubMed  Google Scholar 

  • Karlin D, Ferron F, Canard B, Longhi S (2003) Structural disorder and modular organization in Paramyxovirinae N and P. J Gen Virol 84:3239–3252

    CAS  PubMed  Google Scholar 

  • Karush F (1950) Heterogeneity of the binding sites of bovine serum albumin1. J Am Chem Soc 72:2705–2713

    CAS  Google Scholar 

  • Kriwacki RW, Hengst L, Tennant L, Reed SI, Wright PE (1996) Structural studies of p21Waf1/Cip1/Sdi1 in the free and Cdk2-bound state: conformational disorder mediates binding diversity. Proc Natl Acad Sci USA 93:11504–11509

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar M, Gromiha MM, Raghava GPS (2008) Prediction of RNA binding sites in a protein using SVM and PSSM profle. Proteins 71(1):189–194

    CAS  PubMed  Google Scholar 

  • Landry CR, Levy ED, Michnick SW (2009) Weak functional constraints on phosphoproteomes. Trends Genet 25(5):193–197

    CAS  PubMed  Google Scholar 

  • Lee SH, Kim DH, Han J, Cha EJ, Lim JE, Cho YJ, Lee C, Han KH (2012) Understanding pre-structured motifs (PreSMos) in intrinsically unfolded proteins. Curr Protein Pept Sci 13(1):34–54

    CAS  PubMed  Google Scholar 

  • Leyrat C, Jensen MR, Ribeiro EA (2011) The N0-binding region of the vesicular stomatitis virus phosphoprotein is globally disordered but contains transient α-helices. Protein Sci 20:542–556

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lhomme S, Marion O, Abravanel F, Chapuy-Regaud S, Kamar N, Izopet J (2016) Hepatitis E pathogenesis. Viruses 8(8):212

    PubMed Central  Google Scholar 

  • Li G, La Starza MW, Hardy WR, Strauss JH, Rice CM (1990) Phosphorylation of Sindbis virus nsP3 in vivo and in vitro. Virology 179(1):416–427

    CAS  PubMed  Google Scholar 

  • Lin RJ, Chang BL, Yu HP, Liao CL, Lin YL (2006) Blocking of interferon-induced Jak-Stat signaling by Japanese encephalitis virus NS5 through a protein tyrosine phosphatase-mediated mechanism. J Virol 80(12):5908–5918

    CAS  PubMed  PubMed Central  Google Scholar 

  • Llorente MT, García-Barreno B, Calero M (2006) Structural analysis of the human respiratory syncytial virus phosphoprotein: characterization of an α-helical domain involved in oligomerization. J Gen Virol 87:159–169

    CAS  PubMed  Google Scholar 

  • Macdonald A, Harris M (2004) Hepatitis C virus NS5A: tales of a promiscuous protein. J Gen Virol 85:2485–2502

    CAS  PubMed  Google Scholar 

  • Mann M, Ong SE, Grønborg M, Steen H, Jensen ON, Pandey A (2002) Analysis of protein phosphorylation using mass spectrometry: deciphering the phosphoproteome. Trends Biotechnol 20(6):261–268

    CAS  PubMed  Google Scholar 

  • Marks F (1996) Protein phosphorylation. VCH Weinheim, New York, Basel, Cambridge, Tokyo

  • Meruelo AD, Han SK, Kim S, Bowie JU (2012) Structural differences between thermophilic and mesophilic membrane proteins. Protein Sci 21:1746–1753

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mészáros B, Erdős G, Dosztányi Z (2018) IUPred2A: context-dependent prediction of protein disorder as a function of redox state and protein binding. Nucleic Acids Res 46(W1):W329–W337

    PubMed  PubMed Central  Google Scholar 

  • Mishra PM, Verma NC, Rao C, Uversky VN, Nandi CK (2020) Intrinsically disordered proteins of viruses: Involvement in the mechanism of cell regulation and pathogenesis. Prog Mol Biol Transl Sci 174:1

    PubMed  PubMed Central  Google Scholar 

  • Mohan A, Oldfield CJ, Radivojac P, Vacic V, Cortese MS, Dunker AK, Uversky VN (2006) Analysis of molecular recognition features (MoRFs). J Mol Biol 362(5):1043–1059

    CAS  PubMed  Google Scholar 

  • Mori Y, Matsuura Y (2011) Structure of hepatitis E viral particle. Virus Res 161(1):59–64

    CAS  PubMed  Google Scholar 

  • Nair VP, Anang S, Subramani C, Madhvi A, Bakshi K, Srivastava A, Nayak B, Ranjith Kumar CT, Surjit M (2016) Endoplasmic reticulum stress induced synthesis of a novel viral factor mediates efficient replication of Genotype-1 Hepa-titis E virus. PLoS Pathog 12(4):05521

    Google Scholar 

  • Necci M, Piovesan D, Tosatto SCE (2016) Large-scale analysis of intrinsic disorder flavors and associated functions in the protein sequence universe. Protein Sci 25:2164–2174

    CAS  PubMed  PubMed Central  Google Scholar 

  • Oldfeld CJ, Dunker AK (2014) Intrinsically disordered proteins and intrinsically disordered protein regions. Annu Rev Biochem 83:553–584. https://doi.org/10.1146/annurev-biochem-072711-164947

    Article  CAS  Google Scholar 

  • Parvez MK (2013) Molecular characterization of hepatitis E virus ORF1 gene supports apapain-like cysteine protease (PCP)- domain activity. Virus Res 178(2):553–556

    CAS  PubMed  PubMed Central  Google Scholar 

  • Parvez MK, Al-Dosari MS (2015) Evidence of MAPK-JNK1/2 activation by hepatitis E virus ORF3 protein in cultured hepatoma cells. Cytotechnology 67(3):545–550

    CAS  PubMed  Google Scholar 

  • Peng ZKL (2015) High-throughput prediction of RNA, DNA and protein binding regions mediated by intrinsic disorder. Nucleic Acids Res 43:e121

    PubMed  PubMed Central  Google Scholar 

  • Peng K, Vucetic S, Radivojac P, Brown CJ, Dunker AK, Obradovic Z (2005) Optimizing long intrinsic disorder predictors with protein evolutionary information. J Bioinform Comput Biol 3(01):35–60

    CAS  PubMed  Google Scholar 

  • Peng K, Radivojac P, Vucetic S, Dunker AK, Obradovic Z (2006) Length-dependent prediction of protein intrinsic disorder. BMC Bioinform 7(1):1–17

    CAS  Google Scholar 

  • Peng Z, Wang C, Uversky VN, Kurgan L (2017) Prediction of disordered RNA, DNA, and protein binding regions using DisoRDPbind. Methods Mol Biol 1484:187–203

    CAS  PubMed  Google Scholar 

  • Pérez-Gracia MT, Suay-García B, Mateos-Lindemann ML (2017) Hepatitis E and pregnancy: Current state. Rev Med Virol 27(3):e1929

    PubMed  Google Scholar 

  • Purdy MA, Lara J, Khudyakov YE (2012) The hepatitis E virus polyproline region is involved in viral adaptation. PLoS ONE 7(4):e35974

    CAS  PubMed  PubMed Central  Google Scholar 

  • Radivojac P, Vacic V, Haynes C, Cocklin RR, Mohan A, Heyen JW, Goebl MG, Iakoucheva LM (2010) Identification, analysis and prediction of protein ubiquitination sites. Proteins Struct Funct Bioinform 78(2):365–380

    CAS  Google Scholar 

  • Rajagopal KA, Indira, Tan T (2021) Structure & function–amino acids. https://bio.libretexts.org/@go/page/7809

  • Ramakrishnan C, Ramachandran GN (1965) Stereochemical criteria for polypeptide and protein chain conformations. II. Allowed conformations for a pair of peptide units. Biophys J 5:909–933

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rizzetto M (2009) Hepatitis D: thirty years after. J Hepatol 50(5):1043–1050

    CAS  PubMed  Google Scholar 

  • Romero P, Obradovic Z, Li X et al (2001a) Sequence complexity of disordered protein. Proteins Struct Funct Genet 42(1):38–48

    CAS  PubMed  Google Scholar 

  • Romero P, Obradovic Z, Li X, Garner EC, Brown CJ, Dunker AK (2001b) Sequence complexity of disordered protein. Proteins 42:38–48

    CAS  PubMed  Google Scholar 

  • Roy A, Xu D, Poisson J, Zhang Y (2011) A protocol for computer-based protein structure and function prediction. J Vis Exp;e3259

  • Roy A, Zhang Y (2011) Recognizing protein-ligand binding sites by global structural alignment and local geometry refinement. Structure 20(6):987–997

    Google Scholar 

  • Schweiger R, Linial M (2010) Cooperativity within proximal phosphorylation sites is revealed from large-scale proteomics data. Biol Direct 5(1):1–7

    Google Scholar 

  • Shrestha A, Adhikari A, Bhattarai M, Rauniyar R, Debes JD, Boonstra A, Lama TK, Al Mahtab M, Butt AS, Akbar SM, Aryal N (2017) Prevalence and risk of hepatitis E virus infection in the HIV population of Nepal. Virol J 14(1):1–7

    Google Scholar 

  • Singh A, Kumar A, Yadav R et al (2018) Deciphering the dark proteome of Chikungunya virus. Sci Rep 8:5822

    PubMed  PubMed Central  Google Scholar 

  • Subramani C, Nair VP, Anang S, Mandal SD, Pareek M, Kaushik N, Srivastava A, Saha S, Nayak B, Ranjith-Kumar CT, Surjit M (2018) Host-virus protein interaction network reveals the involvement of multiple host processes in the life cycle of hepatitis E Virus. Msystems 3(1):e00135

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tam AW, Smith MM, Guerra ME, Huang CC, Bradley DW, Fry KE, Reyes GR (1991) Hepatitis E virus (HEV): molecular cloning and sequencing of the full-length viral genome. Virology 185(1):120–131

    CAS  PubMed  Google Scholar 

  • Tavitian S, Peron JM, Huguet F, Kamar N, Abravanel F, Beyne-Rauzy O, Oberic L, Faguer S, Alric L, Roussel M, Gaudin C (2015) Ribavirin for chronic hepatitis prevention among patients with hematologic malignancies. Emerg Infect Dis 21(8):1466

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tompa P (2002) Intrinsically unstructured proteins. Trends Biochem Sci 27:527–533

    CAS  PubMed  Google Scholar 

  • Uversky VN (2002) Natively unfolded proteins: a point where biology waits for physics. Protein Sci 11:739–756

    CAS  PubMed  PubMed Central  Google Scholar 

  • Uversky VN (2011) Intrinsically disordered proteins from A to Z. Int J Biochem Cell Biol 43:1090–1103

    CAS  PubMed  Google Scholar 

  • Uversky VN (2013) Unusual biophysics of intrinsically disordered proteins. Biochim Biophys Acta Proteins Proteom 1834(5):932–951

    CAS  Google Scholar 

  • Vacic V, Uversky VN, Dunker AK, Lonardi S (2007) Composition Profiler: a tool for discovery and visualization of amino acid composition differences. BMC Bioinform 8:211

    Google Scholar 

  • Van Der Lee R, Buljan M, Lang B et al (2014a) Classifcation of intrinsically disordered regions and proteins. Chem Rev 114:6589–6631

    PubMed  PubMed Central  Google Scholar 

  • Van Der Lee R, Buljan M, Lang B, Weatheritt RJ, Daughdrill GW, Dunker AK, Fuxreiter M, Gough J, Gsponer J, Jones DT, Kim PM (2014c) Classifcation of intrinsically disordered regions and proteins. Chem Rev 114:6589–6631

    PubMed  PubMed Central  Google Scholar 

  • Van der Lee R, Lang B, Kruse K, Gsponer J, de Groot NS, Huynen MA, Matouschek A, Fuxreiter M, Babu MM (2014b) Intrinsically disordered segments affect protein half-life in the cell and during evolution. Cell Rep 8:18

    Google Scholar 

  • Verdegem D, Badillo A, Wieruszeski JM (2011) Domain 3 of NS5A protein from the hepatitis C virus has intrinsic α-helical propensity and is a substrate of cyclophilin A. J Biol Chem 286:20441–20454

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vihinen H, Ahola T, Tuittila M, Merits A, Kääriäinen L (2001) Elimination of phosphorylation sites of Semliki Forest virus replicase protein nsP3. J Biol Chem 276(8):5745–5752

    CAS  PubMed  Google Scholar 

  • Wang J, Cao Z, Zhao L, Li S (2011) Novel strategies for drug discovery based on intrinsically disordered proteins (IDPs). Int J Mol Sci 12(5):3205–3219

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ward JJ, Sodhi JS, McGufn LJ et al (2004a) Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol 337:635–645

    CAS  PubMed  Google Scholar 

  • Ward JJ, McGuffin LJ, Bryson K, Buxton BF, Jones DT (2004b) The DISOPRED server for the prediction of protein disorder. Bioinformatics 20:2138–2139

    CAS  PubMed  Google Scholar 

  • Williams RM, Obradovic Z, Mathura V, Braun W, Garner EC, Young J, Takayama S, Brown CJ, Dunker AK (2001) The protein non-folding problem: amino acid determinants of intrinsic order and disorder. Pac Symp Biocomput 2001:89–100

    Google Scholar 

  • Wright PE, Dyson HJ (1999) Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. J Mol Biol 293:321–331

    CAS  PubMed  Google Scholar 

  • Wright PE, Dyson HJ (2009) Linking folding and binding. Curr Opin Struct Biol 19(1):31–38

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wright PE, Dyson HJ (2015) Intrinsically disordered proteins in cellular signalling and regulation. Nat Rev Mol Cell Biol 16(1):18–29

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xue B, Williams RW, Oldfield CJ, Goh GK, Dunker AK, Uversky VN (2010) Viral disorder or disordered viruses: do viral proteins possess unique features? Protein Pept Lett 17:932–951

    CAS  PubMed  Google Scholar 

  • Xue B, Blocquel D, Habchi J (2014) Structural disorder in viral proteins. Chem Rev 114:6880–6911

    CAS  PubMed  Google Scholar 

  • Yan J, Kurgan L (2017a) DRNApred, fast sequence-based method that accurately predicts and discriminates DNA- and RNA-binding residues. Nucleic Acids Res 45(10):e84

    PubMed  PubMed Central  Google Scholar 

  • Yan J, Kurgan L (2017b) DRNApred, fast sequence-based method that accurately predicts and discriminates DNA- and RNA-binding residues. Nucleic Acids Res 45(10):e84–e84

    PubMed  PubMed Central  Google Scholar 

  • Zor T, Mayr BM, Dyson HJ, Montminy MR, Wright PE (2002) Roles of phosphorylation and helix propensity in the binding of the KIX domain of CREB-binding protein by constitutive (c-Myb) and inducible (CREB) activators. J Biol Chem 277(44):42241–42248

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge the Maulana Azad National Fellowship (MANF), University Grant Commission (UGC) and Council of Scientific and Industrial Research (CSIR), (37(1697)17/EMR-II) supported by Government of India.

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Authors and Affiliations

  1. Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India

    Zoya Shafat & Shama Parveen

  2. Centre of Excellence in Biotechnology Research, College of Science, King Saud University, Riyadh, Saudi Arabia

    Anwar Ahmed

  3. Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia

    Mohammad K. Parvez

Authors
  1. Zoya Shafat
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  2. Anwar Ahmed
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  3. Mohammad K. Parvez
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  4. Shama Parveen
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Contributions

SP conceptualized the research. SP and ZS designed the manuscript. ZS was a major contributor in writing the manuscript and performed the biocomputational analysis of the protein. KP and AA proofread the manuscript. All the authors read and approved the final manuscript.

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Correspondence to Shama Parveen.

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Supplementary Information

Below is the link to the electronic supplementary material.

42485_2021_75_MOESM1_ESM.tif

Supplementary file1 (TIF 339 kb) Figure S1 Prediction of disordered residues in ORF4. (A) LC057248 (HEV), (B) KU168733 (Human), (C) JN167538 (Rat) and (D) LC177791 (Ferret). The prediction of disordered residues was carried out using three members of the family PONDR (Prediction of Natural Disordered Regions), i.e., VLXT, VL3 and VSL2. A threshold value of 0.5 was set to distinguish between ordered and disordered region along the genome (dashed line). Regions above the threshold are predicted to be disordered. The predicted disordered residues are shown with alphabet ‘D’

42485_2021_75_MOESM2_ESM.tif

Supplementary file2 (TIF 66 kb) Figure S2 Prediction of disordered residues in ORF4. (A) LC057248 (HEV), (B) KU168733 (Human), (C) JN167538 (Rat) and (D) LC177791 (Ferret). The prediction was carried out using IUPRED2. A threshold value of 0.5 was set to distinguish between ordered and disordered region along the genome (dashed line). Regions above the threshold are predicted to be disordered

42485_2021_75_MOESM3_ESM.tif

Supplementary file3 (TIF 207 kb) Figure S3 Analysis of protein-binding disordered region in ORF4. (A) LC057248 (HEV), (B) KU168733 (Human), (C) JN167538 (Rat) and (D) LC177791 (Ferret). The prediction was carried out using DISOPRED3

42485_2021_75_MOESM4_ESM.tif

Supplementary file4 (TIF 260 kb) Figure S4 Prediction of phosphorylated residues (serine, threonine, tyrosine) and disordered residues in ORF4. (A) LC057248 (HEV) and KU168733 (Human). (B) JN167538 (Rat) and LC177791 (Ferret). The specific amino acid position of the prediction phosphorylated residue was carried out using DEPP (Disorder Enhanced Phosphorylation Predictor). The predicted disordered residues are shown with alphabet ‘D’ while the predicted phosphorylated residues in the ORF1 proteins are marked with asterisk (*). This suggests that most of the phosphorylated residues are present within the disordered regions of the proteins

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Shafat, Z., Ahmed, A., Parvez, M.K. et al. Role of ORF4 in Hepatitis E virus regulation: analysis of intrinsically disordered regions. J Proteins Proteom 12, 289–306 (2021). https://doi.org/10.1007/s42485-021-00075-w

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  • DOI: https://doi.org/10.1007/s42485-021-00075-w

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