Sequential Conformational Changes in the Morbillivirus Attachment Protein Initiate the Membrane Fusion Process

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With the ultimate aim to develop pan-morbillivirus fusion inhibitors, we here characterized a potent neutralizing monoclonal antibody. The antibody recognizes the ectodomain of the membrane-bound tetrameric attachment (H) protein, which together with the fusion protein and a host cell receptor executes plasma membrane fusion to deliver the viral genetic information into the cell. The H-ectodomain consists of a short F-binding/activating stalk region supporting receptor-binding head domains. Molecular characterization of the identified mAb epitope (which locates in the membrane-distal stalk module called “spacer”), enabled us to unravel two sequential conformational changes occurring in CDV H-tetramers that stand at the core of the molecular mechanism translating receptor binding to F-triggering. We additionally propose that both rearrangements are triggered upon receptor-induced “de-activation” of an auto-repressed state assumed by H prior to receptor binding. This locked state enables H/F interaction while preventing premature F-activation. Furthermore, although paramyxovirus attachment proteins may fold into very similar “pre-receptor-bound” conformational states, the presence of the “spacer” module in the stalk emerges as a key determinant leading to distinct mechanisms of membrane fusion triggering.

Vyšlo v časopise: Sequential Conformational Changes in the Morbillivirus Attachment Protein Initiate the Membrane Fusion Process. PLoS Pathog 11(5): e32767. doi:10.1371/journal.ppat.1004880
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004880

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1. Chen SY, Anderson S, Kutty PK, Lugo F, McDonald M, Rota PA, et al. Health care-associated measles outbreak in the United States after an importation: challenges and economic impact. JInfectDis. 2011;203(11):1517–25. doi: 10.1093/infdis/jir115 21531693

2. Plemper RK, Hammond AL. Synergizing vaccinations with therapeutics for measles eradication. ExpertOpinDrug Discov. 2014;9(2):201–14.

3. Krumm SA, Yan D, Hovingh ES, Evers TJ, Enkirch T, Reddy GP, et al. An orally available, small-molecule polymerase inhibitor shows efficacy against a lethal morbillivirus infection in a large animal model. SciTranslMed. 2014;6(232):232ra52.

4. Welsch JC, Talekar A, Mathieu C, Pessi A, Moscona A, Horvat B, et al. Fatal Measles Virus Infection Prevented by Brain-Penetrant Fusion Inhibitors. Journal of virology. 2013;87(24):13785–94. doi: 10.1128/JVI.02436-13 24109233

5. Mathieu C, Huey D, Jurgens E, Welsch JC, DeVito I, Talekar A, et al. Prevention of Measles Virus Infection by Intranasal Delivery of Fusion Inhibitor Peptides. Journal of virology. 2015;89(2):1143–55. doi: 10.1128/JVI.02417-14 25378493

6. Lamb RA, Parks GD. Paramyxoviridae: The viruses and their replication. In: Fileds B, Knipe DM, Howley PM, editors. Fields' Virology, Fifth edition. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 1449–96.

7. Vandevelde M, Zurbriggen A. Demyelination in canine distemper virus infection: a review. Acta Neuropathol(Berl). 2005;109(1):56–68. 15645260

8. Sakai K, Nagata N, Ami Y, Seki F, Suzaki Y, Iwata-Yoshikawa N, et al. Lethal canine distemper virus outbreak in cynomolgus monkeys in Japan in 2008. JVirol. 2013;87(2):1105–14. doi: 10.1128/JVI.02419-12 23135729

9. Kennedy S. Morbillivirus infections in aquatic mammals. JComp Pathol. 1998;119(3):201–25. 9807724

10. Domingo M, Ferrer L, Pumarola M, Marco A, Plana J, Kennedy S, et al. Morbillivirus in dolphins. Nature. 1990;348(6296):21. 2234055

11. Roelke-Parker ME, Munson L, Packer C, Kock R, Cleaveland S, Carpenter M, et al. A canine distemper virus epidemic in Serengeti lions (Panthera leo). Nature. 1996;379(6564):441–5. 8559247

12. Plattet P, Plemper RK. Envelope protein dynamics in paramyxovirus entry. MBio. 2013;4(4).

13. Jardetzky TS, Lamb RA. Activation of paramyxovirus membrane fusion and virus entry. CurrOpinVirol. 2014;5C:24–33.

14. Russell CJ, Jardetzky TS, Lamb RA. Membrane fusion machines of paramyxoviruses: capture of intermediates of fusion. EMBO J. 2001;20(15):4024–34. 11483506

15. Porotto M, DeVito I, Palmer SG, Jurgens EM, Yee JL, Yokoyama CC, et al. Spring-loaded model revisited: paramyxovirus fusion requires engagement of a receptor binding protein beyond initial triggering of the fusion protein. JVirol. 2011;85(24):12867–80. doi: 10.1128/JVI.05873-11 21976650

16. Hashiguchi T, Ose T, Kubota M, Maita N, Kamishikiryo J, Maenaka K, et al. Structure of the measles virus hemagglutinin bound to its cellular receptor SLAM. NatStructMolBiol. 2011;18(2):135–41.

17. Brindley MA, Plemper RK. Blue native PAGE and biomolecular complementation reveal a tetrameric or higher-order oligomer organization of the physiological measles virus attachment protein H. JVirol. 2010;84(23):12174–84. doi: 10.1128/JVI.01222-10 20861270

18. Zhang X, Lu G, Qi J, Li Y, He Y, Xu X, et al. Structure of measles virus hemagglutinin bound to its epithelial receptor nectin-4. NatStructMolBiol. 2013;20(1):67–72.

19. Colf LA, Juo ZS, Garcia KC. Structure of the measles virus hemagglutinin. NatStructMolBiol. 2007;14(12):1227–8. 18026116

20. Hashiguchi T, Kajikawa M, Maita N, Takeda M, Kuroki K, Sasaki K, et al. Crystal structure of measles virus hemagglutinin provides insight into effective vaccines. ProcNatlAcadSciUSA. 2007;104(49):19535–40. 18003910

21. Leonard VH, Sinn PL, Hodge G, Miest T, Devaux P, Oezguen N, et al. Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed. JClinInvest. 2008;118(7):2448–58. doi: 10.1172/JCI35454 18568079

22. Vongpunsawad S, Oezgun N, Braun W, Cattaneo R. Selectively receptor-blind measles viruses: Identification of residues necessary for. JVirol. 2004;78(1):302–13. 14671112

23. Tatsuo H, Ono N, Tanaka K, Yanagi Y. SLAM (CDw150) is a cellular receptor for measles virus. Nature. 2000;406(6798):893–7. 10972291

24. Muhlebach MD, Mateo M, Sinn PL, Prufer S, Uhlig KM, Leonard VH, et al. Adherens junction protein nectin-4 is the epithelial receptor for measles virus. Nature. 2011;480(7378):530–3. doi: 10.1038/nature10639 22048310

25. Noyce RS, Bondre DG, Ha MN, Lin LT, Sisson G, Tsao MS, et al. Tumor cell marker PVRL4 (nectin 4) is an epithelial cell receptor for measles virus. PLoSPathog. 2011;7(8):e1002240. doi: 10.1371/journal.ppat.1002240 21901103

26. Noyce RS, Richardson CD. Nectin 4 is the epithelial cell receptor for measles virus. Trends Microbiol. 2012;20(9):429–39. doi: 10.1016/j.tim.2012.05.006 22721863

27. Tahara M, Takeda M, Shirogane Y, Hashiguchi T, Ohno S, Yanagi Y. Measles virus infects both polarized epithelial and immune cells by using distinctive receptor-binding sites on its hemagglutinin. JVirol. 2008;82(9):4630–7. doi: 10.1128/JVI.02691-07 18287234

28. Langedijk JP, Janda J, Origgi FC, Orvell C, Vandevelde M, Zurbriggen A, et al. Canine distemper virus infects canine keratinocytes and immune cells by using overlapping and distinct regions located on one side of the attachment protein. JVirol. 2011;85(21):11242–54. doi: 10.1128/JVI.05340-11 21849439

29. Zipperle L, Langedijk JP, Orvell C, Vandevelde M, Zurbriggen A, Plattet P. Identification of key residues in virulent canine distemper virus hemagglutinin that control CD150/SLAM-binding activity. JVirol. 2010;84(18):9618–24. doi: 10.1128/JVI.01077-10 20631152

30. von Messling V, Oezguen N, Zheng Q, Vongpunsawad S, Braun W, Cattaneo R. Nearby clusters of hemagglutinin residues sustain SLAM-dependent canine distemper virus entry in peripheral blood mononuclear cells. JVirol. 2005;79(9):5857–62. 15827201

31. Ader N, Brindley MA, Avila M, Origgi FC, Langedijk JP, Orvell C, et al. Structural rearrangements of the central region of the morbillivirus attachment protein stalk domain trigger F protein refolding for membrane fusion. JBiolChem. 2012;287(20):16324–34. doi: 10.1074/jbc.M112.342493 22431728

32. Lee JK, Prussia A, Paal T, White LK, Snyder JP, Plemper RK. Functional interaction between paramyxovirus fusion and attachment proteins. JBiolChem. 2008;283(24):16561–72. doi: 10.1074/jbc.M801018200 18426797

33. Navaratnarajah CK, Negi S, Braun W, Cattaneo R. Membrane fusion triggering: three modules with different structure and function in the upper half of the measles virus attachment protein stalk. JBiolChem. 2012;287(46):38543–51. doi: 10.1074/jbc.M112.410563 23007387

34. Welch BD, Yuan P, Bose S, Kors CA, Lamb RA, Jardetzky TS. Structure of the Parainfluenza Virus 5 (PIV5) Hemagglutinin-Neuraminidase (HN) Ectodomain. PLoSPathog. 2013;9(8):e1003534. doi: 10.1371/journal.ppat.1003534 23950713

35. Bose S, Welch BD, Kors CA, Yuan P, Jardetzky TS, Lamb RA. Structure and mutagenesis of the parainfluenza virus 5 hemagglutinin-neuraminidase stalk domain reveals a four-helix bundle and the role of the stalk in fusion promotion. JVirol. 2011;85(24):12855–66. doi: 10.1128/JVI.06350-11 21994464

36. Yuan P, Swanson KA, Leser GP, Paterson RG, Lamb RA, Jardetzky TS. Structure of the Newcastle disease virus hemagglutinin-neuraminidase (HN) ectodomain reveals a four-helix bundle stalk. ProcNatlAcadSciUSA. 2011;108(36):14920–5. doi: 10.1073/pnas.1111691108 21873198

37. pte-Sengupta S, Navaratnarajah CK, Cattaneo R. Hydrophobic and charged residues in the central segment of the measles virus hemagglutinin stalk mediate transmission of the fusion-triggering signal. JVirol. 2013;87(18):10401–4. doi: 10.1128/JVI.01547-13 23864629

38. Brindley MA, Takeda M, Plattet P, Plemper RK. Triggering the measles virus membrane fusion machinery. ProcNatlAcadSciUSA. 2012;109(44):E3018–E27. doi: 10.1073/pnas.1210925109 23027974

39. Yuan P, Thompson TB, Wurzburg BA, Paterson RG, Lamb RA, Jardetzky TS. Structural studies of the parainfluenza virus 5 hemagglutinin-neuraminidase tetramer in complex with its receptor, sialyllactose. Structure. 2005;13(5):803–15. 15893670

40. Bose S, Song AS, Jardetzky TS, Lamb RA. Fusion activation through attachment protein stalk domains indicates a conserved core mechanism of paramyxovirus entry into cells. JVirol. 2014;88(8):3925–41. doi: 10.1128/JVI.03741-13 24453369

41. Deng R, Wang Z, Mirza AM, Iorio RM. Localization of a domain on the paramyxovirus attachment protein required for the promotion of cellular fusion by its homologous fusion protein spike. Virology. 1995;209(2):457–69. 7778280

42. Tsurudome M, Kawano M, Yuasa T, Tabata N, Nishio M, Komada H, et al. Identification of regions on the hemagglutinin-neuraminidase protein of human parainfluenza virus type 2 important for promoting cell fusion. Virology. 1995;213(1):190–203. 7483263

43. Tanabayashi K, Compans RW. Functional interaction of paramyxovirus glycoproteins: identification of a domain in Sendai virus HN which promotes cell fusion. JVirol. 1996;70(9):6112–8. 8709235

44. Deng R, Mirza AM, Mahon PJ, Iorio RM. Functional chimeric HN glycoproteins derived from Newcastle disease virus and human parainfluenza virus-3. ArchVirolSuppl. 1997;13:115–30.

45. Wang Z, Mirza AM, Li J, Mahon PJ, Iorio RM. An oligosaccharide at the C-terminus of the F-specific domain in the stalk of the human parainfluenza virus 3 hemagglutinin-neuraminidase modulates fusion. Virus Res. 2004;99(2):177–85. 14749183

46. Bose S, Zokarkar A, Welch BD, Leser GP, Jardetzky TS, Lamb RA. Fusion activation by a headless parainfluenza virus 5 hemagglutinin-neuraminidase stalk suggests a modular mechanism for triggering. ProcNatlAcadSciUSA. 2012;109(39):E2625–E34. 22949640

47. Brindley MA, Suter R, Schestak I, Kiss G, Wright ER, Plemper RK. A stabilized headless measles virus attachment protein stalk efficiently triggers membrane fusion. JVirol. 2013;87(21):11693–703. doi: 10.1128/JVI.01945-13 23966411

48. Brindley MA, Chaudhury S, Plemper RK. Measles Virus Glycoprotein Complexes Preassemble Intracellularly and Relax during Transport to the Cell Surface in Preparation for Fusion. Journal of virology. 2015;89(2):1230–41. doi: 10.1128/JVI.02754-14 25392208

49. Liu Q, Stone JA, Bradel-Tretheway B, Dabundo J, avides Montano JA, Santos-Montanez J, et al. Unraveling a three-step spatiotemporal mechanism of triggering of receptor-induced Nipah virus fusion and cell entry. PLoSPathog. 2013;9(11):e1003770. doi: 10.1371/journal.ppat.1003770 24278018

50. Paterson RG, Johnson ML, Lamb RA. Paramyxovirus fusion (F) protein and hemagglutinin-neuraminidase (HN) protein interactions: intracellular retention of F and HN does not affect transport of the homotypic HN or F protein. Virology. 1997;237(1):1–9. 9344902

51. Bose S, Heath CM, Shah PA, Alayyoubi M, Jardetzky TS, Lamb RA. Mutations in the parainfluenza virus 5 fusion protein reveal domains important for fusion triggering and metastability. JVirol. 2013;87(24):13520–31. doi: 10.1128/JVI.02123-13 24089572

52. Plemper RK, Hammond AL, Cattaneo R. Measles virus envelope glycoproteins hetero-oligomerize in the endoplasmic reticulum. JBiolChem. 2001;276(47):44239–46. 11535597

53. Aguilar HC, Matreyek KA, Choi DY, Filone CM, Young S, Lee B. Polybasic KKR motif in the cytoplasmic tail of Nipah virus fusion protein modulates membrane fusion by inside-out signaling. JVirol. 2007;81(9):4520–32. 17301148

54. Aguilar HC, Matreyek KA, Filone CM, Hashimi ST, Levroney EL, Negrete OA, et al. N-glycans on Nipah virus fusion protein protect against neutralization but reduce membrane fusion and viral entry. JVirol. 2006;80(10):4878–89. 16641279

55. Bishop KA, Stantchev TS, Hickey AC, Khetawat D, Bossart KN, Krasnoperov V, et al. Identification of Hendra virus G glycoprotein residues that are critical for receptor binding. JVirol. 2007;81(11):5893–901. 17376907

56. Plattet P, Langedijk JP, Zipperle L, Vandevelde M, Orvell C, Zurbriggen A. Conserved leucine residue in the head region of morbillivirus fusion protein regulates the large conformational change during fusion activity. Biochemistry. 2009;48(38):9112–21. doi: 10.1021/bi9008566 19705836

57. Paal T, Brindley MA, St CC, Prussia A, Gaus D, Krumm SA, et al. Probing the spatial organization of measles virus fusion complexes. JVirol. 2009;83(20):10480–93. doi: 10.1128/JVI.01195-09 19656895

58. Porotto M, Palmer SG, Palermo LM, Moscona A. Mechanism of fusion triggering by human parainfluenza virus type III: communication between viral glycoproteins during entry. JBiolChem. 2012;287(1):778–93. doi: 10.1074/jbc.M111.298059 22110138

59. Xu R, Palmer SG, Porotto M, Palermo LM, Niewiesk S, Wilson IA, et al. Interaction between the hemagglutinin-neuraminidase and fusion glycoproteins of human parainfluenza virus type III regulates viral growth in vivo. MBio. 2013;4(5):e00803–e13. doi: 10.1128/mBio.00803-13 24149514

60. Porotto M, Salah ZW, Gui L, DeVito I, Jurgens EM, Lu H, et al. Regulation of paramyxovirus fusion activation: the hemagglutinin-neuraminidase protein stabilizes the fusion protein in a pre-triggered state. JVirol. 2012.

61. Orvell C, Sheshberadaran H, Norrby E. Preparation and characterization of monoclonal antibodies directed against four structural components of canine distemper virus. JGenVirol. 1985;66 (Pt 3):443–56. 2579191

62. Avila M, Alves L, Khosravi M, der-Ebert N, Origgi F, Schneider-Schaulies J, et al. Molecular determinants defining the triggering range of prefusion F complexes of canine distemper virus. JVirol. 2014;88(5):2951–66. doi: 10.1128/JVI.03123-13 24371057

63. Ader N, Brindley M, Avila M, Orvell C, Horvat B, Hiltensperger G, et al. Mechanism for active membrane fusion triggering by morbillivirus attachment protein. JVirol. 2013;87(1):314–26. doi: 10.1128/JVI.01826-12 23077316

64. Corey EA, Iorio RM. Mutations in the stalk of the measles virus hemagglutinin protein decrease fusion but do not interfere with virus-specific interaction with the homologous fusion protein. JVirol. 2007;81(18):9900–10. 17626104

65. Navaratnarajah CK, Kumar S, Generous A, pte-Sengupta S, Mateo M, Cattaneo R. The measles virus hemagglutinin stalk: structures and functions of the central fusion activation and membrane-proximal segments. JVirol. 2014;88(11):6158–67. doi: 10.1128/JVI.02846-13 24648460

66. Talekar A, DeVito I, Salah Z, Palmer SG, Chattopadhyay A, Rose JK, et al. Identification of a region in the stalk domain of the nipah virus receptor binding protein that is critical for fusion activation. JVirol. 2013;87(20):10980–96. doi: 10.1128/JVI.01646-13 23903846

67. Plemper RK, Hammond AL, Gerlier D, Fielding AK, Cattaneo R. Strength of envelope protein interaction modulates cytopathicity of measles virus. JVirol. 2002;76(10):5051–61. 11967321

68. Avila M, Khosravi M, Alves L, Ader-Ebert N, Bringolf F, Zurbriggen A, et al. Canine Distemper Virus Envelope Protein Interactions Modulated by Hydrophobic Residues in the Fusion Protein Globular Head. Journal of virology. 2015;89(2):1445–51. doi: 10.1128/JVI.01828-14 25355896

69. Welch BD, Paduch M, Leser GP, Bergman Z, Kors CA, Paterson RG, et al. Probing the functions of the paramyxovirus glycoproteins F and HN with a panel of synthetic antibodies (sABs). JVirol. 2014.

70. Gui L, Jurgens EM, Ebner JL, Porotto M, Moscona A, Lee KK. Electron tomography imaging of surface glycoproteins on human parainfluenza virus 3: association of receptor binding and fusion proteins before receptor engagement. mBio. 2015;6(1):e02393–14. doi: 10.1128/mBio.02393-14 25691596

71. Cherpillod P, Beck K, Zurbriggen A, Wittek R. Sequence analysis and expression of the attachment and fusion proteins of canine distemper virus wild-type strain A75/17. JVirol. 1999;73(3):2263–9. 9971809

72. Origgi FC, Plattet P, Sattler U, Robert N, Casaubon J, Mavrot F, et al. Emergence of canine distemper virus strains with modified molecular signature and enhanced neuronal tropism leading to high mortality in wild carnivores. VetPathol. 2012;49(6):913–29. doi: 10.1177/0300985812436743 22362965

73. Wiener D, Plattet P, Cherpillod P, Zipperle L, Doherr MG, Vandevelde M, et al. Synergistic inhibition in cell-cell fusion mediated by the matrix and nucleocapsid protein of canine distemper virus. Virus Res. 2007;129(2):145–54. 17706826

74. Plattet P, Cherpillod P, Wiener D, Zipperle L, Vandevelde M, Wittek R, et al. Signal peptide and helical bundle domains of virulent canine distemper virus fusion protein restrict fusogenicity. JVirol. 2007;81(20):11413–25. 17686846

75. Navaratnarajah CK, Oezguen N, Rupp L, Kay L, Leonard VH, Braun W, et al. The heads of the measles virus attachment protein move to transmit the fusion-triggering signal. NatStructMolBiol. 2011;18(2):128–34.