Role of “dual-personality” fragments in HEV adaptation—analysis of Y-domain region
Tóm tắt
Hepatitis E is a liver disease caused by the pathogen hepatitis E virus (HEV). The largest polyprotein open reading frame 1 (ORF1) contains a nonstructural Y-domain region (YDR) whose activity in HEV adaptation remains uncharted. The specific role of disordered regions in several nonstructural proteins has been demonstrated to participate in the multiplication and multiple regulatory functions of the viruses. Thus, intrinsic disorder of YDR including its structural and functional annotation was comprehensively studied by exploiting computational methodologies to delineate its role in viral adaptation. Based on our findings, it was evident that YDR contains significantly higher levels of ordered regions with less prevalence of disordered residues. Sequence-based analysis of YDR revealed it as a “dual personality” (DP) protein due to the presence of both structured and unstructured (intrinsically disordered) regions. The evolution of YDR was shaped by pressures that lead towards predominance of both disordered and regularly folded amino acids (Ala, Arg, Gly, Ile, Leu, Phe, Pro, Ser, Tyr, Val). Additionally, the predominance of characteristic DP residues (Thr, Arg, Gly, and Pro) further showed the order as well as disorder characteristic possessed by YDR. The intrinsic disorder propensity analysis of YDR revealed it as a moderately disordered protein. All the YDR sequences consisted of molecular recognition features (MoRFs), i.e., intrinsic disorder-based protein–protein interaction (PPI) sites, in addition to several nucleotide-binding sites. Thus, the presence of molecular recognition (PPI, RNA binding, and DNA binding) signifies the YDR’s interaction with specific partners, host membranes leading to further viral infection. The presence of various disordered-based phosphorylation sites further signifies the role of YDR in various biological processes. Furthermore, functional annotation of YDR revealed it as a multifunctional-associated protein, due to its susceptibility in binding to a wide range of ligands and involvement in various catalytic activities. As DP are targets for regulation, thus, YDR contributes to cellular signaling processes through PPIs. As YDR is incompletely understood, therefore, our data on disorder-based function could help in better understanding its associated functions. Collectively, our novel data from this comprehensive investigation is the first attempt to delineate YDR role in the regulation and pathogenesis of HEV.
Tài liệu tham khảo
Khuroo MS (2011) Discovery of hepatitis E: the epidemic non-A, non-B hepatitis 30 years down the memory lane. Virus Res 161(1):3–14.
Khuroo MS, Kamili S (2003) Aetiology, clinical course and outcome of sporadic acute viral hepatitis in pregnancy. J Viral Hepat 10(1):61–69.
Li P, Liu J, Li Y, Su J, Ma Z, Bramer WM, Cao W, de Man RA, Peppelenbosch MP, Pan Q (2020) The global epidemiology of hepatitis E virus infection: a systematic review and meta-analysis. Liver International 40(7):1516–1528.
Teshale EH, Hu DJ, Holmberg SD (2010) The two faces of hepatitis E virus. Clin Infect Dis 51(3):328–334.
Meng XJ (2011) From barnyard to food table: the omnipresence of hepatitis E virus and risk for zoonotic infection and food safety. Virus Res 161(1):23–30.
Yugo DM, Cossaboom CM, Heffron CL, Huang YW, Kenney SP, Woolums AR, Hurley DJ, Opriessnig T, Li L, Delwart E, Kanevsky I (2019) Evidence for an unknown agent antigenically related to the hepatitis E virus in dairy cows in the United States. J Med Virol 91(4):677–686.
Sanford BJ, Emerson SU, Purcell RH, Engle RE, Dryman BA, Cecere TE, Buechner-Maxwell V, Sponenberg DP, Meng XJ (2013) Serological evidence for a hepatitis E virus (HEV)-related agent in goats in the United States. Transbound Emerg Dis 60(6):538–545.
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.
Wang Y, Chen G, Pan Q, Zhao (2018) Chronic hepatitis E in a renal transplant recipient: the first report of genotype 4 hepatitis E virus caused chronic infection in organ recipient. Gastroenteroloy 154(4):1199–1201.
Takahashi K, Terada S, Kokuryu H, Arai M, Mishiro S (2010) A wild boar-derived hepatitis E virus isolate presumably representing so far unidentified “genotype 5”. Kanzo 51(9):536–538.
Takahashi M, Nishizawa T, Sato H, Sato Y, Nagashima S, Okamoto H (2011) Analysis of the full-length genome of a hepatitis E virus isolate obtained from a wild boar in Japan that is classifiable into a novel genotype. J Gen Virol 92(4):902–908.
Rasche A, Saqib M, Liljander AM, Bornstein S, Zohaib A, Renneker S, Steinhagen K, Wernery R, Younan M, Gluecks I, Hilali M (2016) Hepatitis E virus infection in dromedaries, North and East Africa, United Arab Emirates, and Pakistan, 1983–2015. Emerg Infect Dis 22(7):1249–1252.
Woo PC, Lau SK, Teng JL, Tsang AK, Joseph M, Wong EY, Tang Y, Sivakumar S, Xie J, Bai R, Wernery R (2014) New hepatitis E virus genotype in camels, the Middle East. Emerg Infect Dis 20(6):1044–1048.
Meng XJ (2016) Expanding host range and cross-species infection of hepatitis E virus. PLoS Pathog 12(8):e1005695.
Westhölter D, Hiller J, Denzer U, Polywka S, Ayuk F, Rybczynski M, Horvatits T, Gundlach S, Blöcker J, Zur Wiesch JS, Fischer N (2018) HEV-positive blood donations represent a relevant infection risk for immunosuppressed recipients. J Hepatol 69(1):36–42.
Teshale EH, Grytdal SP, Howard C, Barry V, Kamili S, Drobeniuc J, Hill VR, Okware S, Hu DJ, Holmberg SD (2010) Evidence of person-to-person transmission of hepatitis E virus during a large outbreak in Northern Uganda. Clin Infect Dis 50(7):1006–1010.
Zeng MY, Gao H, Yan XX, Qu WJ, Sun YK, Fu GW, Yan YL (2017) High hepatitis E virus antibody positive rates in dogs and humans exposed to dogs in the south-west of China. Zoonoses Public Health 64(8):684–688.
Liang H, Chen J, Xie J, Sun L, Ji F, He S, Zheng Y, Liang C, Zhang G, Su S, Li S (2014) Hepatitis E virus serosurvey among pet dogs and cats in several developed cities in China. PLoS ONE 9(6):e98068.
Aggarwal R (2013) Diagnosis of hepatitis E. Nat Rev Gastroenterol Hepatol 10(1):24–33.
Takahashi M, Kusakai S, Mizuo H, Suzuki K, Fujimura K, Masuko K, Sugai Y, Aikawa T, Nishizawa T, Okamoto H (2005) Simultaneous detection of immunoglobulin a (IgA) and IgM antibodies against hepatitis E virus (HEV) is highly specific for diagnosis of acute HEV infection. J Clin Microbiol 43(1):49–56.
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.
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.
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.
Chandra V, Taneja S, Kalia M, Jameel S (2008) Molecular biology and pathogenesis of hepatitis E virus. J Biosci 33(4):451–464.
Mori Y, Matsuura Y (2011) Structure of hepatitis E viral particle. Virus Res 161(1):59–64.
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):1–3.
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.
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.
Parvez MK (2017) The hepatitis E virus nonstructural polyprotein. Future Microbiol 12(10):915–924.
Parvez MK (2017) Mutational analysis of hepatitis E virus ORF1 “Y-domain”: effects on RNA replication and virion infectivity. World J Gastroenterol 23(4):590–602.
Van Der Lee R, Buljan M, Lang B, Weatheritt RJ, Daughdrill GW, Dunker AK, Fuxreiter M, Gough J, Gsponer J, Jones DT, Kim PM (2014) Classification of intrinsically disordered regions and proteins. Chem Rev 114(13):6589–6631.
Oldfeld CJ, Dunker AK (2014) Intrinsically disordered proteins and intrinsically disordered protein regions. Annu Rev Biochem 83(1):553–584.
Wright PE, Dyson HJ (1999) Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. J Mol Biol 293(2):321–331.
Dyson HJ, Wright PE (2005) Intrinsically unstructured proteins and their functions. Nature Reviews Molec Cell Biol 6(3):197–208.
Dyson HJ, Wright PE (2002) Coupling of folding and binding for unstructured proteins. Curr Opin Struct Biol 12(1):54–60.
Uversky VN (2002) Natively unfolded proteins: a point where biology waits for physics. Protein Sci 11(4):739–756.
Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJ (2015) The Phyre2 web portal for protein modeling, prediction and analysis. Nature protocols 10(6):845–858.
Peng K, Radivojac P, Vucetic S, Dunker AK, Obradovic Z (2006) Length-dependent prediction of protein intrinsic disorder. BMC Bioinformatics 7 7(1):1–17
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.
Romero P, Obradovic Z, Li X, Garner EC, Brown CJ, Dunker AK (2001) Sequence complexity of disordered protein. Proteins Struct Funct Genet 42(1):38–48.
Disfani FM, Hsu W-L, Mizianty MJ, Oldfield CJ, Xue B, Dunker AK, Uversky VN, Kurgan L (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.
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.
Yan J, Kurgan L (2017) DRNApred, fast sequence-based method that accurately predicts and discriminates DNA- and RNA-binding residues. Nucleic Acids Res 45(10):e84–e84.
Kumar M, Gromiha MM, Raghava GPS (2008) Prediction of RNA binding sites in a protein using SVM and PSSM profile. Proteins 71(1):189–194.
Roy A, Xu D, Poisson J, Zhang Y (2011) A protocol for computer-based protein structure and function prediction. J Vis Exp. e3259 p.
Roy A, Zhang Y (2011) Recognizing protein-ligand binding sites by global structural alignment and local geometry refinement. Structure 20(6):987–997
Zhang Y, Stec B, Godzik A (2007) Between order and disorder in protein structures: analysis of “dual personality” fragments in proteins. Structure 15(9):1141–1147.
Uversky VN, Dunker AK (2010) Understanding protein non-folding. Biochim Biophys Acta 1804:1231–64
Radivojac P, Iakoucheva LM, Oldfield CJ, Obradovic Z, Uversky VN, Dunker AK (2007) Intrinsic disorder and functional proteomics. Biophys J 92:1439–56
Campen A, Williams RM, Brown CJ, Meng J, Uversky VN, Dunker AK (2008) TOP-IDP-scale: a new amino acid scale measuring propensity for intrinsic disorder. Protein Pept Lett 15:956–63
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
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
Romero P, Obradovic Z, Li X, Garner EC, Brown CJ, Dunker AK (2001) Sequence complexity of disordered protein. Proteins 42:38–48
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 9:201–13
Gsponer J, Futschik ME, Teichmann SA, Babu MM (2008) Tight regulation of unstructured proteins: from transcript synthesis to protein degradation. Science 322(5906):1365–1368.
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.
Li X, Obradovic Z, Brown CJ, Garner EC, Dunker AC (2000) Comparing predictors of disordered protein. Genome Informatics 11:172–184
Xue B, Blocquel D, Habchi J (2014) Structural disorder in viral proteins. Chem Rev 114(13):6880–6911.
Moutinho AF, Trancoso FF, Dutheil JY (2019) The impact of protein architecture on adaptive evolution. Molecular biology and evolution 36(9):2013–2028.
Shafat Z, Hamza A, Islam A, Al-Dosari MS, Parvez MK, Parveen S (2021) Structural exploration of Y-domain reveals its essentiality in HEV pathogenesis. Protein Expr Purif 105947
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 (2001) Intrinsically disordered protein. J Mol Graph Model 19(1):26–59.
Garner E, Romero P, Dunker AK, Brown C, Obradovic Z (1999) Predicting binding regions within disordered proteins. Genome Inform 10:41–50
Schweiger R, Linial M (2010) Cooperativity within proximal phosphorylation sites is revealed from large-scale proteomics data. Biol. Direct 5(1):1–7.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
Marks F (1996) Protein phosphorylation. VCH Weinheim, New York, Basel, Cambridge, Tokyo.
Keck F, Ataey P, Amaya M, Bailey C, Narayanan A (2015) Phosphorylation of single stranded RNA virus proteins and potential for novel therapeutic strategies. Viruses 7(10):5257–73
Iakoucheva LM, Radivojac P, Brown CJ, O’Connor TR, Sikes JG, Obradovic Z, Dunker AK (2004) The importance of intrinsic disorder for protein phosphorylation. Nucleic Acids Res 32(3):1037–1049.
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 Proteomics. 7(7):1331–1348.
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.
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.
Rajagopal, K. A., Indira, & Tan, T. (2021) Structure & function - amino acids. from https://bio.libretexts.org/@go/page/7809
Wang T, Weinman SA (2013) Interactions between hepatitis C virus and mitochondria: impact on pathogenesis and innate immunity. Curr Pathobiol Rep 1(3):179–187.
Mills EL, Kelly B, O'Neill LA (2017) Mitochondria are the powerhouses of immunity. Nat. Immunol. 18(5):488–498.
Kim SJ, Ahn DG, Syed GH, Siddiqui A (2018) The essential role of mitochondrial dynamics in antiviral immunity. Mitochondrion 41:21–27.
Ma X, Jin M, Cai Y, Xia H, Long K, Liu J, Yu Q, Yuan J (2011) Mitochondrial electron transport chain complex III is required for antimycin A to inhibit autophagy. Chem Biol 18(11):1474–1481.
Khutornenko AA, Roudko VV, Chernyak BV, Vartapetian AB, Chumakov PM, Evstafieva AG (2010) Pyrimidine biosynthesis links mitochondrial respiration to the p53 pathway. Proc Natl Acad Sci USA 107(29):12828–12833.
Qu C, Zhang S, Wang W, Li M, Wang Y, van der Heijde-Mulder M, Shokrollahi E, Hakim MS, Raat NJ, Peppelenbosch MP, Pan Q (2019) Mitochondrial electron transport chain complex III sustains hepatitis E virus replication and represents an antiviral target. FASEB J 33(1):1008–1019.
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. Progress in molecular biology and translational science. 174:1.
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(18):9267–9277.
De Chassey B, Navratil V, Tafforeau L (2008) Hepatitis C virus infection protein network. Mol Syst Biol 4(1):230.
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
Macdonald A, Harris M (2004) Hepatitis C virus NS5A: tales of a promiscuous protein. J Gen Virol 85(9):2485–2502.
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(2):251–262.
Karlin D, Ferron F, Canard B, Longhi S (2003) Structural disorder and modular organization in Paramyxovirinae N and P. J Gen Virol 84(12):3239–3252.
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(1):159–169.
Gerard FCA, Ribeiro EA, Leyrat C (2009) Modular organization of rabies virus phosphoprotein. J Mol Biol 388(5):978–996.
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(3):542–556.
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(20):10374–10383.
Habchi J, Longhi S (2012) Structural disorder within paramyxovirus nucleoproteins and phosphoproteins. Mol Biosyst 8(1):69–81.
Purdy MA, Lara J, Khudyakov YE (2012) The hepatitis E virus polyproline region is involved in viral adaptation. PloS one 7(4):e35974.