Cellular and Molecular Life Sciences

, Volume 76, Issue 3, pp 577–608 | Cite as

Structural disorder in the proteome and interactome of Alkhurma virus (ALKV)

  • Elrashdy M. RedwanEmail author
  • Abdullah A. AlJaddawi
  • Vladimir N. UverskyEmail author
Original Article


Infection by the Alkhurma virus (ALKV) leading to the Alkhurma hemorrhagic fever is a common thread in Saudi Arabia, with no efficient treatment or prevention available as of yet. Although the rational drug design traditionally uses information on known 3D structures of viral proteins, intrinsically disordered proteins (i.e., functional proteins that do not possess unique 3D structures), with their multitude of disorder-dependent functions, are crucial for the biology of viruses. Here, viruses utilize disordered regions in their invasion of the host organisms and in hijacking and repurposing of different host systems. Furthermore, the ability of viruses to efficiently adjust and accommodate to their hostile habitats is also intrinsic disorder-dependent. However, little is currently known on the level of penetrance and functional utilization of intrinsic disorder in the ALKV proteome. To fill this gap, we used here multiple computational tools to evaluate the abundance of intrinsic disorder in the ALKV genome polyprotein. We also analyzed the peculiarities of intrinsic disorder predisposition of the individual viral proteins, as well as human proteins known to be engaged in interaction with the ALKV proteins. Special attention was paid to finding a correlation between protein functionality and structural disorder. To the best of our knowledge, this work represents the first systematic study of the intrinsic disorder status of ALKV proteome and interactome.


Intrinsically disordered protein Alkhurma virus Proteome Protein structure Protein function Protein folding Partially folded conformation Protein–protein interactions Interactome 



This work was supported by the Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, under Grant no. D1439-128-130. The authors, therefore, gratefully acknowledge the DSR technical and financial support.

Supplementary material

18_2018_2968_MOESM1_ESM.docx (17.9 mb)
Supplementary material 1 (DOCX 18295 kb)


  1. 1.
    Alzahrani AG, Al Shaiban HM, Al Mazroa MA, Al-Hayani O, Macneil A, Rollin PE, Memish ZA (2010) Alkhurma hemorrhagic fever in humans, Najran, Saudi Arabia. Emerg Infect Dis 16:1882–1888Google Scholar
  2. 2.
    Madani TA, Azhar EI, Abuelzein el TM, Kao M, Al-Bar HM, Abu-Araki H, Niedrig M, Ksiazek TG (2011) Alkhumra (Alkhurma) virus outbreak in Najran, Saudi Arabia: epidemiological, clinical, and laboratory characteristics. J Infect 62:67–76Google Scholar
  3. 3.
    Qattan I, Akbar N, Afif H, Azmah SA, Khateeb T, Zaki A (1996) A novel flavivirus: Makkah region 1994–1996. Saudi Epidemiol Bull 1:2–3Google Scholar
  4. 4.
    Zaki AM (1997) Isolation of a flavivirus related to the tick-borne encephalitis complex from human cases in Saudi Arabia. Trans R Soc Trop Med Hyg 91:179–181Google Scholar
  5. 5.
    Madani TA (2005) Alkhumra virus infection, a new viral hemorrhagic fever in Saudi Arabia. J Infect 51:91–97Google Scholar
  6. 6.
    Gaunt MW, Sall AA, de Lamballerie X, Falconar AK, Dzhivanian TI, Gould EA (2001) Phylogenetic relationships of flaviviruses correlate with their epidemiology, disease association and biogeography. J Gen Virol 82:1867–1876Google Scholar
  7. 7.
    Grard G, Moureau G, Charrel RN, Lemasson JJ, Gonzalez JP, Gallian P, Gritsun TS, Holmes EC, Gould EA, de Lamballerie X (2007) Genetic characterization of tick-borne flaviviruses: new insights into evolution, pathogenetic determinants and taxonomy. Virology 361:80–92Google Scholar
  8. 8.
    Heinze DM, Gould EA, Forrester NL (2012) Revisiting the clinal concept of evolution and dispersal for the tick-borne flaviviruses by using phylogenetic and biogeographic analyses. J Virol 86:8663–8671Google Scholar
  9. 9.
    Moureau G, Cook S, Lemey P, Nougairede A, Forrester NL, Khasnatinov M, Charrel RN, Firth AE, Gould EA, de Lamballerie X (2015) New insights into flavivirus evolution, taxonomy and biogeographic history, extended by analysis of canonical and alternative coding sequences. PLoS One 10:e0117849Google Scholar
  10. 10.
    Pulkkinen LIA, Butcher SJ, Anastasina M (2018) Tick-borne encephalitis virus: a structural view. Viruses 10:E350Google Scholar
  11. 11.
    Madani TA, Abuelzein EM, Jalalah SM, Abu-Araki H, Azhar EI, Hassan AM, Al-Bar HM (2017) Electron microscopy of Alkhumra hemorrhagic fever virus. Vector Borne Zoonotic Dis 17:195–199Google Scholar
  12. 12.
    Lindenbach BD, Thiel H-J, Rice CM (2007) Flaviviridae: the viruses and their replication. In: Knipe D, Howley P (eds) Fields virology. Lippincott-Raven Publishers, Philadelphia, pp 1101–1152Google Scholar
  13. 13.
    Meng F, Badierah RA, Almehdar HA, Redwan EM, Kurgan L, Uversky VN (2015) Unstructural biology of the Dengue virus proteins. FEBS J 282:3368–3394Google Scholar
  14. 14.
    Giri R, Kumar D, Sharma N, Uversky VN (2016) Intrinsically disordered side of the Zika virus proteome. Front Cell Infect Microbiol 6:144Google Scholar
  15. 15.
    Deresinski S (2010) Alkhurma hemorrhagic fever virus: an emerging pathogen. Clin Infect Dis 51:viGoogle Scholar
  16. 16.
    Xue B, Dunker AK, Uversky VN (2012) Orderly order in protein intrinsic disorder distribution: disorder in 3500 proteomes from viruses and the three domains of life. J Biomol Struct Dyn 30:137–149Google Scholar
  17. 17.
    Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P, Oh JS, Oldfield CJ, Campen AM, Ratliff CM, Hipps KW, Ausio 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 19:26–59Google Scholar
  18. 18.
    Dunker AK, Obradovic Z, Romero P, Garner EC, Brown CJ (2000) Intrinsic protein disorder in complete genomes. Genome Inform Ser Workshop Genome Inform 11:161–171Google Scholar
  19. 19.
    Tompa P (2002) Intrinsically unstructured proteins. Trends Biochem Sci 27:527–533Google Scholar
  20. 20.
    Uversky VN (2002) Natively unfolded proteins: a point where biology waits for physics. Protein Sci 11:739–756Google Scholar
  21. 21.
    Uversky VN (2010) The mysterious unfoldome: structureless, underappreciated, yet vital part of any given proteome. J Biomed Biotechnol 2010:568068Google Scholar
  22. 22.
    Uversky VN, Dunker AK (1804) Understanding protein non-folding. Biochim Biophys Acta 2010:1231–1264Google Scholar
  23. 23.
    Uversky VN, Gillespie JR, Fink AL (2000) Why are “natively unfolded” proteins unstructured under physiologic conditions? Proteins 41:415–427Google Scholar
  24. 24.
    Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN (2005) Flexible nets. The roles of intrinsic disorder in protein interaction networks. FEBS J 272:5129–5148Google Scholar
  25. 25.
    Ward JJ, Sodhi JS, McGuffin LJ, Buxton BF, Jones DT (2004) Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol 337:635–645Google Scholar
  26. 26.
    Dunker AK, Obradovic Z (2001) The protein trinity—linking function and disorder. Nat Biotechnol 19:805–806Google Scholar
  27. 27.
    Uversky VN (1834) Unusual biophysics of intrinsically disordered proteins. Biochim Biophys Acta 2013:932–951Google Scholar
  28. 28.
    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 1998:473–484Google Scholar
  29. 29.
    Wright PE, Dyson HJ (1999) Intrinsically unstructured proteins: re-assessing the protein structure–function paradigm. J Mol Biol 293:321–331Google Scholar
  30. 30.
    Daughdrill GW, Pielak GJ, Uversky VN, Cortese MS, Dunker AK (2005) Natively disordered proteins. In: Buchner J, Kiefhaber T (eds) Handbook of protein folding. Wiley-VCH, New York, pp 271–353Google Scholar
  31. 31.
    Iakoucheva LM, Brown CJ, Lawson JD, Obradovic Z, Dunker AK (2002) Intrinsic disorder in cell-signaling and cancer-associated proteins. J Mol Biol 323:573–584Google Scholar
  32. 32.
    Dyson HJ, Wright PE (2005) Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol 6:197–208Google Scholar
  33. 33.
    Tompa P (2005) The interplay between structure and function in intrinsically unstructured proteins. FEBS Lett 579:3346–3354Google Scholar
  34. 34.
    Radivojac P, Iakoucheva LM, Oldfield CJ, Obradovic Z, Uversky VN, Dunker AK (2007) Intrinsic disorder and functional proteomics. Biophys J 92:1439–1456Google Scholar
  35. 35.
    Vucetic S, Xie H, Iakoucheva LM, Oldfield CJ, Dunker AK, Obradovic Z, Uversky VN (2007) Functional anthology of intrinsic disorder. 2. Cellular components, domains, technical terms, developmental processes, and coding sequence diversities correlated with long disordered regions. J Proteome Res 6:1899–1916Google Scholar
  36. 36.
    Xie H, Vucetic S, Iakoucheva LM, Oldfield CJ, Dunker AK, Obradovic Z, Uversky VN (2007) Functional anthology of intrinsic disorder. 3. Ligands, post-translational modifications, and diseases associated with intrinsically disordered proteins. J Proteome Res 6:1917–1932Google Scholar
  37. 37.
    Xie H, Vucetic S, Iakoucheva LM, Oldfield CJ, Dunker AK, Uversky VN, Obradovic Z (2007) Functional anthology of intrinsic disorder. 1. Biological processes and functions of proteins with long disordered regions. J Proteome Res 6:1882–1898Google Scholar
  38. 38.
    Uversky VN, Oldfield CJ, Dunker AK (2008) Intrinsically disordered proteins in human diseases: introducing the D2 concept. Annu Rev Biophys 37:215–246Google Scholar
  39. 39.
    Vacic V, Markwick PR, Oldfield CJ, Zhao X, Haynes C, Uversky VN, Iakoucheva LM (2012) Disease-associated mutations disrupt functionally important regions of intrinsic protein disorder. PLoS Comput Biol 8:e1002709Google Scholar
  40. 40.
    Tokuriki N, Oldfield CJ, Uversky VN, Berezovsky IN, Tawfik DS (2009) Do viral proteins possess unique biophysical features? Trends Biochem Sci 34:53–59Google Scholar
  41. 41.
    Fan X, Xue B, Dolan PT, LaCount DJ, Kurgan L, Uversky VN (2014) The intrinsic disorder status of the human hepatitis C virus proteome. Mol BioSyst 10:1345–1363Google Scholar
  42. 42.
    Xue B, Mizianty MJ, Kurgan L, Uversky VN (2012) Protein intrinsic disorder as a flexible armor and a weapon of HIV-1. Cell Mol Life Sci 69:1211–1259Google Scholar
  43. 43.
    Uversky VN, Roman A, Oldfield CJ, Dunker AK (2006) Protein intrinsic disorder and human papillomaviruses: increased amount of disorder in E6 and E7 oncoproteins from high risk HPVs. J Proteome Res 5:1829–1842Google Scholar
  44. 44.
    Xue B, Ganti K, Rabionet A, Banks L, Uversky VN (2014) Disordered interactome of human papillomavirus. Curr Pharm Des 20:1274–1292Google Scholar
  45. 45.
    Mishra PM, Uversky VN, Giri R (2018) Molecular recognition features in Zika virus proteome. J Mol Biol 430:2372–2388Google Scholar
  46. 46.
    Whelan JN, Reddy KD, Uversky VN, Teng MN (2016) Functional correlations of respiratory syncytial virus proteins to intrinsic disorder. Mol BioSyst 12:1507–1526Google Scholar
  47. 47.
    Goh GK, Dunker AK, Uversky V (2013) Prediction of intrinsic disorder in MERS-CoV/HCoV-EMC supports a high oral-fecal transmission. PLoS Curr 5:1–22Google Scholar
  48. 48.
    T.U. Consortium (2014) Activities at the Universal Protein Resource (UniProt). Nucleic Acids Res 42:D191–D198Google Scholar
  49. 49.
    Orchard S, Ammari M, Aranda B, Breuza L, Briganti L, Broackes-Carter F, Campbell NH, Chavali G, Chen C, del-Toro N, Duesbury M, Dumousseau M, Galeota E, Hinz U, Iannuccelli M, Jagannathan S, Jimenez R, Khadake J, Lagreid A, Licata L, Lovering RC, Meldal B, Melidoni AN, Milagros M, Peluso D, Perfetto L, Porras P, Raghunath A, Ricard-Blum S, Roechert B, Stutz A, Tognolli M, van Roey K, Cesareni G, Hermjakob H (2014) The MIntAct project–IntAct as a common curation platform for 11 molecular interaction databases. Nucleic Acids Res 42:D358–D363Google Scholar
  50. 50.
    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 15:956–963Google Scholar
  51. 51.
    Vacic V, Uversky VN, Dunker AK, Lonardi S (2007) Composition Profiler: a tool for discovery and visualization of amino acid composition differences. BMC Bioinform 8:211Google Scholar
  52. 52.
    Sievers F, Wilm A, Dineen D, Gibson TJ, Karplus K, Li W, Lopez R, McWilliam H, Remmert M, Söding J, Thompson JD, Higgins DG (2011) Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol 7:539Google Scholar
  53. 53.
    Dinkel H, Van Roey K, Michael S, Davey NE, Weatheritt RJ, Born D, Speck T, Krüger D, Grebnev G, Kubań M, Strumillo M, Uyar B, Budd A, Altenberg B, Seiler M, Chemes LB, Glavina J, Sánchez IE, Diella F, Gibson TJ (2014) The eukaryotic linear motif resource ELM: 10 years and counting. Nucleic Acids Res 42:D259–D266Google Scholar
  54. 54.
    Romero P, Obradovic Z, Li X, Garner EC, Brown CJ, Dunker AK (2001) Sequence complexity of disordered protein. Proteins 42:38–48Google Scholar
  55. 55.
    Peng K, Radivojac P, Vucetic S, Dunker AK, Obradovic Z (2006) Length-dependent prediction of protein intrinsic disorder. BMC Bioinform 7:208Google Scholar
  56. 56.
    Xue B, Dunbrack RL, Williams RW, Dunker AK, Uversky VN (1804) PONDR-FIT: a meta-predictor of intrinsically disordered amino acids. Biochim Biophys Acta 2010:996–1010Google Scholar
  57. 57.
    Dosztanyi Z, Csizmok V, Tompa P, Simon I (2005) IUPred: web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content. Bioinformatics 21:3433–3434Google Scholar
  58. 58.
    Dosztanyi Z, Csizmok V, Tompa P, Simon I (2005) The pairwise energy content estimated from amino acid composition discriminates between folded and intrinsically unstructured proteins. J Mol Biol 347:827–839Google Scholar
  59. 59.
    Meszaros B, Simon I, Dosztanyi Z (2009) Prediction of protein binding regions in disordered proteins. PLoS Comput Biol 5:e1000376Google Scholar
  60. 60.
    Dosztanyi Z, Meszaros B, Simon I (2009) ANCHOR: web server for predicting protein binding regions in disordered proteins. Bioinformatics 25:2745–2746Google Scholar
  61. 61.
    Dayhoff MO, Schwartz RM, Orcutt BC (1978) A model of evolutionary change in proteins. Atlas Protein Seq Struct 5:345–351Google Scholar
  62. 62.
    Gould CM, Diella F, Vian A, Puntervoll P, Gemünd C, Chabanis-Davidson S, Michael S, Sayadi A, Bryne JC, Chica C, Seiler M, Davey NE, Haslam N, Weatheritt RJ, Budd A, Hughes T, Paś J, Rychlewski L, Travé G, Aasland R, Helmer-Citterich M, Linding R, Gibson TJ (2010) ELM: the status of the 2010 eukaryotic linear motif resource. Nucleic Acids Res 38:D167–D180Google Scholar
  63. 63.
    Mizianty MJ, Zhang T, Xue B, Zhou Y, Dunker AK, Uversky VN, Kurgan L (2011) In-silico prediction of disorder content using hybrid sequence representation. BMC Bioinform 12:245Google Scholar
  64. 64.
    Peng ZL, Kurgan L (2012) Comprehensive comparative assessment of in silico predictors of disordered regions. Curr Protein Pept Sci 13:6–18Google Scholar
  65. 65.
    Fan X, Kurgan L (2014) Accurate prediction of disorder in protein chains with a comprehensive and empirically designed consensus. J Biomol Struct Dyn 32:448–464Google Scholar
  66. 66.
    Obradovic Z, Peng K, Vucetic S, Radivojac P, Brown CJ, Dunker AK (2003) Predicting intrinsic disorder from amino acid sequence. Proteins 53(Suppl 6):566–572Google Scholar
  67. 67.
    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 3:35–60Google Scholar
  68. 68.
    Prilusky J, Felder CE, Zeev-Ben-Mordehai T, Rydberg EH, Man O, Beckmann JS, Silman I, Sussman JL (2005) FoldIndex: a simple tool to predict whether a given protein sequence is intrinsically unfolded. Bioinformatics 21:3435–3438Google Scholar
  69. 69.
    Walsh I, Giollo M, Di Domenico T, Ferrari C, Zimmermann O, Tosatto SC (2015) Comprehensive large-scale assessment of intrinsic protein disorder. Bioinformatics 31:201–208Google Scholar
  70. 70.
    Peng Z, Kurgan L (2012) On the complementarity of the consensus-based disorder prediction. Pac Symp Biocomput 2012:176–187Google Scholar
  71. 71.
    Alonso-Lopez D, Gutierrez MA, Lopes KP, Prieto C, Santamaria R, De Las Rivas J (2016) APID interactomes: providing proteome-based interactomes with controlled quality for multiple species and derived networks. Nucleic Acids Res 44:W529–W535Google Scholar
  72. 72.
    Chatr-Aryamontri A, Breitkreutz BJ, Oughtred R, Boucher L, Heinicke S, Chen D, Stark C, Breitkreutz A, Kolas N, O’Donnell L, Reguly T, Nixon J, Ramage L, Winter A, Sellam A, Chang C, Hirschman J, Theesfeld C, Rust J, Livstone MS, Dolinski K, Tyers M (2015) The BioGRID interaction database: 2015 update. Nucleic Acids Res 43(2015):D470–D478Google Scholar
  73. 73.
    Salwinski L, Miller CS, Smith AJ, Pettit FK, Bowie JU, Eisenberg D (2004) The Database of Interacting Proteins: 2004 update. Nucleic Acids Res 32(2004):D449–D451Google Scholar
  74. 74.
    Keshava Prasad TS, Goel R, Kandasamy K, Keerthikumar S, Kumar S, Mathivanan S, Telikicherla D, Raju R, Shafreen B, Venugopal A, Balakrishnan L, Marimuthu A, Banerjee S, Somanathan DS, Sebastian A, Rani S, Ray S, Harrys Kishore CJ, Kanth S, Ahmed M, Kashyap MK, Mohmood R, Ramachandra YL, Krishna V, Rahiman BA, Mohan S, Ranganathan P, Ramabadran S, Chaerkady R, Pandey A (2009) Human Protein Reference Database—2009 update. Nucleic Acids Res 37:D767–D772Google Scholar
  75. 75.
    Kerrien S, Aranda B, Breuza L, Bridge A, Broackes-Carter F, Chen C, Duesbury M, Dumousseau M, Feuermann M, Hinz U, Jandrasits C, Jimenez RC, Khadake J, Mahadevan U, Masson P, Pedruzzi I, Pfeiffenberger E, Porras P, Raghunath A, Roechert B, Orchard S, Hermjakob H (2012) The IntAct molecular interaction database in 2012. Nucleic Acids Res 40:D841–D846Google Scholar
  76. 76.
    Licata L, Briganti L, Peluso D, Perfetto L, Iannuccelli M, Galeota E, Sacco F, Palma A, Nardozza AP, Santonico E, Castagnoli L, Cesareni G (2012) MINT, the molecular interaction database: 2012 update. Nucleic Acids Res 40(2012):D857–D861Google Scholar
  77. 77.
    Huttlin EL, Ting L, Bruckner RJ, Gebreab F, Gygi MP, Szpyt J, Tam S, Zarraga G, Colby G, Baltier K, Dong R, Guarani V, Vaites LP, Ordureau A, Rad R, Erickson BK, Wuhr M, Chick J, Zhai B, Kolippakkam D, Mintseris J, Obar RA, Harris T, Artavanis-Tsakonas S, Sowa ME, De Camilli P, Paulo JA, Harper JW, Gygi SP (2015) The BioPlex Network: a systematic exploration of the human interactome. Cell 162:425–440Google Scholar
  78. 78.
    Rose PW, Prlic A, Bi C, Bluhm WF, Christie CH, Dutta S, Green RK, Goodsell DS, Westbrook JD, Woo J, Young J, Zardecki C, Berman HM, Bourne PE, Burley SK (2015) The RCSB Protein Data Bank: views of structural biology for basic and applied research and education. Nucleic Acids Res 43:D345–D356Google Scholar
  79. 79.
    Uversky VN (2002) What does it mean to be natively unfolded? Eur J Biochem 269:2–12Google Scholar
  80. 80.
    Uversky VN (2003) Protein folding revisited. A polypeptide chain at the folding-misfolding-nonfolding cross-roads: which way to go? Cell Mol Life Sci 60:1852–1871Google Scholar
  81. 81.
    Uversky VN (2013) A decade and a half of protein intrinsic disorder: biology still waits for physics. Protein Sci 22:693–724Google Scholar
  82. 82.
    Vucetic S, Obradovic Z, Vacic V, Radivojac P, Peng K, Iakoucheva LM, Cortese MS, Lawson JD, Brown CJ, Sikes JG, Newton CD, Dunker AK (2005) DisProt: a database of protein disorder. Bioinformatics 21:137–140Google Scholar
  83. 83.
    Sickmeier M, Hamilton JA, LeGall T, Vacic V, Cortese MS, Tantos A, Szabo B, Tompa P, Chen J, Uversky VN, Obradovic Z, Dunker AK (2007) DisProt: the database of disordered proteins. Nucleic Acids Res 35:D786–D793Google Scholar
  84. 84.
    Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The Protein Data Bank. Nucleic Acids Res 28:235–242Google Scholar
  85. 85.
    de Laureto PP, Tosatto L, Frare E, Marin O, Uversky VN, Fontana A (2006) Conformational properties of the SDS-bound state of alpha-synuclein probed by limited proteolysis: unexpected rigidity of the acidic C-terminal tail. Biochemistry 45:11523–11531Google Scholar
  86. 86.
    Fontana A, de Laureto PP, Spolaore B, Frare E, Picotti P, Zambonin M (2004) Probing protein structure by limited proteolysis. Acta Biochim Polon 51:299–321Google Scholar
  87. 87.
    Fontana A, Fassina G, Vita C, Dalzoppo D, Zamai M, Zambonin M (1986) Correlation between sites of limited proteolysis and segmental mobility in thermolysin. Biochemistry 25:1847–1851Google Scholar
  88. 88.
    Fontana A, Polverino de Laureto P, De Filippis V, Scaramella E, Zambonin M (1997) Probing the partly folded states of proteins by limited proteolysis. Fold Des 2:R17–R26Google Scholar
  89. 89.
    Iakoucheva LM, Kimzey AL, Masselon CD, Bruce JE, Garner EC, Brown CJ, Dunker AK, Smith RD, Ackerman EJ (2001) Identification of intrinsic order and disorder in the DNA repair protein XPA. Protein Sci 10:560–571Google Scholar
  90. 90.
    Polverino de Laureto P, De Filippis V, Di Bello M, Zambonin M, Fontana A (1995) Probing the molten globule state of alpha-lactalbumin by limited proteolysis. Biochemistry 34:12596–12604Google Scholar
  91. 91.
    Rodenhuis-Zybert IA, Wilschut J, Smit JM (2011) Partial maturation: an immune-evasion strategy of dengue virus? Trends Microbiol 19:248–254Google Scholar
  92. 92.
    Stohlman SA, Wisseman CL Jr, Eylar OR, Silverman DJ (1975) Dengue virus-induced modifications of host cell membranes. J Virol 16:1017–1026Google Scholar
  93. 93.
    Perera R, Kuhn RJ (2008) Structural proteomics of dengue virus. Curr Opin Microbiol 11:369–377Google Scholar
  94. 94.
    Oliveira ERA, Mohana-Borges R, de Alencastro RB, Horta BAC (2017) The flavivirus capsid protein: structure, function and perspectives towards drug design. Virus Res 227:115–123Google Scholar
  95. 95.
    Zhang X, Ge P, Yu X, Brannan JM, Bi G, Zhang Q, Schein S, Zhou ZH (2013) Cryo-EM structure of the mature dengue virus at 3.5-A resolution. Nat Struct Mol Biol 20:105–110Google Scholar
  96. 96.
    Kuhn RJ, Zhang W, Rossmann MG, Pletnev SV, Corver J, Lenches E, Jones CT, Mukhopadhyay S, Chipman PR, Strauss EG, Baker TS, Strauss JH (2002) Structure of dengue virus: implications for flavivirus organization, maturation, and fusion. Cell 108:717–725Google Scholar
  97. 97.
    Bhuvanakantham R, Chong MK, Ng ML (2009) Specific interaction of capsid protein and importin-alpha/beta influences West Nile virus production. Biochem Biophys Res Commun 389:63–69Google Scholar
  98. 98.
    Colpitts TM, Barthel S, Wang P, Fikrig E (2011) Dengue virus capsid protein binds core histones and inhibits nucleosome formation in human liver cells. PLoS One 6:e24365Google Scholar
  99. 99.
    Poenisch M, Metz P, Blankenburg H, Ruggieri A, Lee JY, Rupp D, Rebhan I, Diederich K, Kaderali L, Domingues FS, Albrecht M, Lohmann V, Erfle H, Bartenschlager R (2015) Identification of HNRNPK as regulator of hepatitis C virus particle production. PLoS Pathog 11:e1004573Google Scholar
  100. 100.
    Netsawang J, Noisakran S, Puttikhunt C, Kasinrerk W, Wongwiwat W, Malasit P, Yenchitsomanus PT, Limjindaporn T (2010) Nuclear localization of dengue virus capsid protein is required for DAXX interaction and apoptosis. Virus Res 147:275–283Google Scholar
  101. 101.
    Balinsky CA, Schmeisser H, Ganesan S, Singh K, Pierson TC, Zoon KC (2013) Nucleolin interacts with the dengue virus capsid protein and plays a role in formation of infectious virus particles. J Virol 87:13094–13106Google Scholar
  102. 102.
    Samuel GH, Wiley MR, Badawi A, Adelman ZN, Myles KM (2016) Yellow fever virus capsid protein is a potent suppressor of RNA silencing that binds double-stranded RNA. Proc Natl Acad Sci USA 113:13863–13868Google Scholar
  103. 103.
    Konishi E, Mason PW (1993) Proper maturation of the Japanese encephalitis virus envelope glycoprotein requires cosynthesis with the premembrane protein. J Virol 67:1672–1675Google Scholar
  104. 104.
    Lorenz IC, Allison SL, Heinz FX, Helenius A (2002) Folding and dimerization of tick-borne encephalitis virus envelope proteins prM and E in the endoplasmic reticulum. J Virol 76:5480–5491Google Scholar
  105. 105.
    Guirakhoo F, Heinz FX, Mandl CW, Holzmann H, Kunz C (1991) Fusion activity of flaviviruses: comparison of mature and immature (prM-containing) tick-borne encephalitis virions. J Gen Virol 72(Pt 6):1323–1329Google Scholar
  106. 106.
    Zhang Y, Corver J, Chipman PR, Zhang W, Pletnev SV, Sedlak D, Baker TS, Strauss JH, Kuhn RJ, Rossmann MG (2003) Structures of immature flavivirus particles. EMBO J 22:2604–2613Google Scholar
  107. 107.
    Heinz FX, Stiasny K, Puschner-Auer G, Holzmann H, Allison SL, Mandl CW, Kunz C (1994) Structural changes and functional control of the tick-borne encephalitis virus glycoprotein E by the heterodimeric association with protein prM. Virology 198:109–117Google Scholar
  108. 108.
    Guirakhoo F, Bolin RA, Roehrig JT (1992) The Murray Valley encephalitis virus prM protein confers acid resistance to virus particles and alters the expression of epitopes within the R2 domain of E glycoprotein. Virology 191:921–931Google Scholar
  109. 109.
    Roby JA, Setoh YX, Hall RA, Khromykh AA (2015) Post-translational regulation and modifications of flavivirus structural proteins. J Gen Virol 96:1551–1569Google Scholar
  110. 110.
    Catteau A, Roue G, Yuste VJ, Susin SA, Despres P (2003) Expression of dengue ApoptoM sequence results in disruption of mitochondrial potential and caspase activation. Biochimie 85:789–793Google Scholar
  111. 111.
    Pierson TC, Diamond MS (2012) Degrees of maturity: the complex structure and biology of flaviviruses. Curr Opin Virol 2:168–175Google Scholar
  112. 112.
    Yu IM, Zhang W, Holdaway HA, Li L, Kostyuchenko VA, Chipman PR, Kuhn RJ, Rossmann MG, Chen J (2008) Structure of the immature dengue virus at low pH primes proteolytic maturation. Science 319:1834–1837Google Scholar
  113. 113.
    Murray CL, Jones CT, Rice CM (2008) Architects of assembly: roles of Flaviviridae non-structural proteins in virion morphogenesis. Nat Rev Microbiol 6:699–708Google Scholar
  114. 114.
    Brand C, Bisaillon M, Geiss BJ (2017) Organization of the Flavivirus RNA replicase complex. Wiley Interdiscip Rev RNA 8:e1437Google Scholar
  115. 115.
    Muller DA, Young PR (2013) The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker. Antiviral Res 98:192–208Google Scholar
  116. 116.
    Mackenzie JM, Jones MK, Young PR (1996) Immunolocalization of the dengue virus nonstructural glycoprotein NS1 suggests a role in viral RNA replication. Virology 220:232–240Google Scholar
  117. 117.
    Muylaert IR, Chambers TJ, Galler R, Rice CM (1996) Mutagenesis of the N-linked glycosylation sites of the yellow fever virus NS1 protein: effects on virus replication and mouse neurovirulence. Virology 222:159–168Google Scholar
  118. 118.
    Xie X, Gayen S, Kang C, Yuan Z, Shi PY (2013) Membrane topology and function of dengue virus NS2A protein. J Virol 87:4609–4622Google Scholar
  119. 119.
    Klema VJ, Padmanabhan R, Choi KH (2015) Flaviviral replication complex: coordination between RNA Synthesis and 5′-RNA Capping. Viruses 7:4640–4656Google Scholar
  120. 120.
    Falgout B, Pethel M, Zhang YM, Lai CJ (1991) Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins. J Virol 65:2467–2475Google Scholar
  121. 121.
    Wang CC, Huang ZS, Chiang PL, Chen CT, Wu HN (2009) Analysis of the nucleoside triphosphatase, RNA triphosphatase, and unwinding activities of the helicase domain of dengue virus NS3 protein. FEBS Lett 583:691–696Google Scholar
  122. 122.
    Miller S, Kastner S, Krijnse-Locker J, Buhler S, Bartenschlager R (2007) The non-structural protein 4A of dengue virus is an integral membrane protein inducing membrane alterations in a 2K-regulated manner. J Biol Chem 282:8873–8882Google Scholar
  123. 123.
    Umareddy I, Chao A, Sampath A, Gu F, Vasudevan SG (2006) Dengue virus NS4B interacts with NS3 and dissociates it from single-stranded RNA. J Gen Virol 87:2605–2614Google Scholar
  124. 124.
    Youn S, Li T, McCune BT, Edeling MA, Fremont DH, Cristea IM, Diamond MS (2012) Evidence for a genetic and physical interaction between nonstructural proteins NS1 and NS4B that modulates replication of West Nile virus. J Virol 86:7360–7371Google Scholar
  125. 125.
    Zmurko J, Neyts J, Dallmeier K (2015) Flaviviral NS4b, chameleon and jack-in-the-box roles in viral replication and pathogenesis, and a molecular target for antiviral intervention. Rev Med Virol 25:205–223Google Scholar
  126. 126.
    Issur M, Geiss BJ, Bougie I, Picard-Jean F, Despins S, Mayette J, Hobdey SE, Bisaillon M (2009) The flavivirus NS5 protein is a true RNA guanylyltransferase that catalyzes a two-step reaction to form the RNA cap structure. RNA 15:2340–2350Google Scholar
  127. 127.
    Egloff MP, Benarroch D, Selisko B, Romette JL, Canard B (2002) An RNA cap (nucleoside-2′-O-)-methyltransferase in the flavivirus RNA polymerase NS5: crystal structure and functional characterization. EMBO J 21:2757–2768Google Scholar
  128. 128.
    Chu PW, Westaway EG (1985) Replication strategy of Kunjin virus: evidence for recycling role of replicative form RNA as template in semiconservative and asymmetric replication. Virology 140:68–79Google Scholar
  129. 129.
    Bollati M, Alvarez K, Assenberg R, Baronti C, Canard B, Cook S, Coutard B, Decroly E, de Lamballerie X, Gould EA, Grard G, Grimes JM, Hilgenfeld R, Jansson AM, Malet H, Mancini EJ, Mastrangelo E, Mattevi A, Milani M, Moureau G, Neyts J, Owens RJ, Ren J, Selisko B, Speroni S, Steuber H, Stuart DI, Unge T, Bolognesi M (2010) Structure and functionality in flavivirus NS-proteins: perspectives for drug design. Antiviral Res 87:125–148Google Scholar
  130. 130.
    Best SM (2017) The many faces of the flavivirus NS5 protein in antagonism of type I interferon signaling. J Virol 91:e1970-16Google Scholar
  131. 131.
    Uversky VN (2013) Intrinsic disorder-based protein interactions and their modulators. Curr Pharm Des 19:4191–4213Google Scholar
  132. 132.
    Uversky VN (2017) Looking at the recent advances in understanding alpha-synuclein and its aggregation through the proteoform prism. F1000Res 6:525Google Scholar
  133. 133.
    Uversky VN (2016) p53 proteoforms and intrinsic disorder: an illustration of the protein structure–function continuum concept. Int J Mol Sci 17:E1874Google Scholar
  134. 134.
    DeForte S, Uversky VN (2016) Order, disorder, and everything in between, molecules. Molecules 21:E1090Google Scholar
  135. 135.
    Uversky VN (2016) Dancing protein clouds: the strange biology and chaotic physics of intrinsically disordered proteins. J Biol Chem 291:6681–6688Google Scholar
  136. 136.
    Oldfield CJ, Cheng Y, Cortese MS, Romero P, Uversky VN, Dunker AK (2005) Coupled folding and binding with alpha-helix-forming molecular recognition elements. Biochemistry 44:12454–12470Google Scholar
  137. 137.
    Mohan A, Oldfield CJ, Radivojac P, Vacic V, Cortese MS, Dunker AK, Uversky VN (2006) Analysis of molecular recognition features (MoRFs). J Mol Biol 362:1043–1059Google Scholar
  138. 138.
    Vacic V, Oldfield CJ, Mohan A, Radivojac P, Cortese MS, Uversky VN, Dunker AK (2007) Characterization of molecular recognition features, MoRFs, and their binding partners. J Proteome Res 6:2351–2366Google Scholar
  139. 139.
    Cheng Y, Oldfield CJ, Meng J, Romero P, Uversky VN, Dunker AK (2007) Mining alpha-helix-forming molecular recognition features with cross species sequence alignments. Biochemistry 46:13468–13477Google Scholar
  140. 140.
    Le Breton M, Meyniel-Schicklin L, Deloire A, Coutard B, Canard B, de Lamballerie X, Andre P, Rabourdin-Combe C, Lotteau V, Davoust N (2011) Flavivirus NS3 and NS5 proteins interaction network: a high-throughput yeast two-hybrid screen. BMC Microbiol 11:234Google Scholar
  141. 141.
    Rajagopalan K, Mooney SM, Parekh N, Getzenberg RH, Kulkarni P (2011) A majority of the cancer/testis antigens are intrinsically disordered proteins. J Cell Biochem 112:3256–3267Google Scholar
  142. 142.
    Patil A, Nakamura H (2006) Disordered domains and high surface charge confer hubs with the ability to interact with multiple proteins in interaction networks. FEBS Lett 580:2041–2045Google Scholar
  143. 143.
    Haynes C, Oldfield CJ, Ji F, Klitgord N, Cusick ME, Radivojac P, Uversky VN, Vidal M, Iakoucheva LM (2006) Intrinsic disorder is a common feature of hub proteins from four eukaryotic interactomes. PLoS Comput Biol 2:e100Google Scholar
  144. 144.
    Ekman D, Light S, Bjorklund AK, Elofsson A (2006) What properties characterize the hub proteins of the protein-protein interaction network of Saccharomyces cerevisiae? Genome Biol 7:R45Google Scholar
  145. 145.
    Dosztanyi Z, Chen J, Dunker AK, Simon I, Tompa P (2006) Disorder and sequence repeats in hub proteins and their implications for network evolution. J Proteome Res 5:2985–2995Google Scholar
  146. 146.
    Singh GP, Ganapathi M, Sandhu KS, Dash D (2006) Intrinsic unstructuredness and abundance of PEST motifs in eukaryotic proteomes. Proteins 62:309–315Google Scholar
  147. 147.
    Oates ME, Romero P, Ishida T, Ghalwash M, Mizianty MJ, Xue B, Dosztanyi Z, Uversky VN, Obradovic Z, Kurgan L, Dunker AK, Gough J (2013) D(2)P(2): database of disordered protein predictions. Nucleic Acids Res 41:D508–D516Google Scholar
  148. 148.
    Ishida T, Kinoshita K (2007) PrDOS: prediction of disordered protein regions from amino acid sequence. Nucleic Acids Res 35:W460–W464Google Scholar
  149. 149.
    Obradovic Z, Peng K, Vucetic S, Radivojac P, Dunker AK (2005) Exploiting heterogeneous sequence properties improves prediction of protein disorder. Proteins 61(Suppl 7):176–182Google Scholar
  150. 150.
    Walsh I, Martin AJ, Di Domenico T, Tosatto SC (2012) ESpritz: accurate and fast prediction of protein disorder. Bioinformatics 28:503–509Google Scholar
  151. 151.
    Habchi J, Tompa P, Longhi S, Uversky VN (2014) Introducing protein intrinsic disorder. Chem Rev 114:6561–6588Google Scholar
  152. 152.
    van der Lee R, Buljan M, Lang B, Weatheritt RJ, Daughdrill GW, Dunker AK, Fuxreiter M, Gough J, Gsponer J, Jones DT, Kim PM, Kriwacki RW, Oldfield CJ, Pappu RV, Tompa P, Uversky VN, Wright PE, Babu MM (2014) Classification of intrinsically disordered regions and proteins. Chem Rev 114:6589–6631Google Scholar
  153. 153.
    Uversky VN (2011) Multitude of binding modes attainable by intrinsically disordered proteins: a portrait gallery of disorder-based complexes. Chem Soc Rev 40:1623–1634Google Scholar
  154. 154.
    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 32:1037–1049Google Scholar
  155. 155.
    Pejaver V, Hsu WL, Xin F, Dunker AK, Uversky VN, Radivojac P (2014) The structural and functional signatures of proteins that undergo multiple events of post-translational modification. Protein Sci 23:1077–1093Google Scholar
  156. 156.
    Tompa P, Szasz C, Buday L (2005) Structural disorder throws new light on moonlighting. Trends Biochem Sci 30:484–489Google Scholar
  157. 157.
    Hwang SS, Boyle TJ, Lyerly HK, Cullen BR (1991) Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1. Science 253:71–74Google Scholar
  158. 158.
    Wu L, Gerard NP, Wyatt R, Choe H, Parolin C, Ruffing N, Borsetti A, Cardoso AA, Desjardin E, Newman W, Gerard C, Sodroski J (1996) CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature 384:179–183Google Scholar
  159. 159.
    Gorry PR, Ancuta P (2011) Coreceptors and HIV-1 pathogenesis. Curr HIV/AIDS Rep 8:45–53Google Scholar
  160. 160.
    Regoes RR, Bonhoeffer S (2005) The HIV coreceptor switch: a population dynamical perspective. Trends Microbiol 13:269–277Google Scholar
  161. 161.
    Jiang X, Feyertag F, Robertson DL (2017) Protein structural disorder of the envelope V3 loop contributes to the switch in human immunodeficiency virus type 1 cell tropism. PLoS One 12:e0185790Google Scholar
  162. 162.
    Goo L, DeMaso CR, Pelc RS, Ledgerwood JE, Graham BS, Kuhn RJ, Pierson TC (2018) The Zika virus envelope protein glycan loop regulates virion antigenicity. Virology 515:191–202Google Scholar
  163. 163.
    Abd-Jamil J, Cheah CY, AbuBakar S (2008) Dengue virus type 2 envelope protein displayed as recombinant phage attachment protein reveals potential cell binding sites. Protein Eng Des Sel 21:605–611Google Scholar
  164. 164.
    Li C, Zhang LY, Sun MX, Li PP, Huang L, Wei JC, Yao YL, Isahg H, Chen PY, Mao X (2012) Inhibition of Japanese encephalitis virus entry into the cells by the envelope glycoprotein domain III (EDIII) and the loop3 peptide derived from EDIII. Antiviral Res 94:179–183Google Scholar
  165. 165.
    Oldfield CJ, Xue B, Van YY, Ulrich EL, Markley JL, Dunker AK, Uversky VN (1834) Utilization of protein intrinsic disorder knowledge in structural proteomics. Biochim Biophys Acta 2012:487–498Google Scholar
  166. 166.
    Reeves R, Nissen MS (1999) Purification and assays for high mobility group HMG-I(Y) protein function. Methods Enzymol 304:155–188Google Scholar
  167. 167.
    Stewart AA, Ingebritsen TS, Cohen P (1983) The protein phosphatases involved in cellular regulation. 5. Purification and properties of a Ca2+/calmodulin-dependent protein phosphatase (2B) from rabbit skeletal muscle. Eur J Biochem 132:289–295Google Scholar
  168. 168.
    Bandaru V, Cooper W, Wallace SS, Doublie S (2004) Overproduction, crystallization and preliminary crystallographic analysis of a novel human DNA-repair enzyme that recognizes oxidative DNA damage. Acta Crystallogr D Biol Crystallogr 60:1142–1144Google Scholar
  169. 169.
    Petros AM, Medek A, Nettesheim DG, Kim DH, Yoon HS, Swift K, Matayoshi ED, Oltersdorf T, Fesik SW (2001) Solution structure of the antiapoptotic protein bcl-2. Proc Natl Acad Sci USA 98:3012–3017Google Scholar
  170. 170.
    Harauz G, Ishiyama N, Hill CM, Bates IR, Libich DS, Fares C (2004) Myelin basic protein-diverse conformational states of an intrinsically unstructured protein and its roles in myelin assembly and multiple sclerosis. Micron 35:503–542Google Scholar
  171. 171.
    Bailey RW, Dunker AK, Brown CJ, Garner EC, Griswold MD (2001) Clusterin, a binding protein with a molten globule-like region. Biochemistry 40:11828–11840Google Scholar
  172. 172.
    Daughdrill GW, Chadsey MS, Karlinsey JE, Hughes KT, Dahlquist FW (1997) The C-terminal half of the anti-sigma factor, FlgM, becomes structured when bound to its target, sigma 28. Nat Struct Biol 4:285–291Google Scholar
  173. 173.
    Cary PD, King DS, Crane-Robinson C, Bradbury EM, Rabbani A, Goodwin GH, Johns EW (1980) Structural studies on two high-mobility-group proteins from calf thymus, HMG-14 and HMG-20 (ubiquitin), and their interaction with DNA. Eur J Biochem 112:577–580Google Scholar

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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Biological Sciences, Faculty of SciencesKing Abdulaziz UniversityJeddahSaudi Arabia
  2. 2.Department of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of MedicineUniversity of South FloridaTampaUSA
  3. 3.Laboratory of New Methods in BiologyInstitute for Biological Instrumentation, Russian Academy of SciencesPushchinoRussia

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