This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lavillette, D.
Right arrow Articles by Cosset, F.-L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lavillette, D.
Right arrow Articles by Cosset, F.-L.

 Previous Article  |  Next Article 

Journal of Virology, October 2002, p. 9673-9685, Vol. 76, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.19.9673-9685.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Relationship between SU Subdomains That Regulate the Receptor-Mediated Transition from the Native (Fusion-Inhibited) to the Fusion-Active Conformation of the Murine Leukemia Virus Glycoprotein

Dimitri Lavillette,{dagger} Alessia Ruggieri, Bertrand Boson, Marielle Maurice, and François-Loïc Cosset*

Laboratoire de Vectorologie Rétrovirale et Thérapie Génique, INSERM U412, IFR 74, Ecole Normale Supérieure de Lyon, Lyon, France

Received 12 April 2002/ Accepted 1 July 2002

Envelope glycoproteins (Env) of retroviruses are trimers of SU (surface) and TM (transmembrane) heterodimers and are expressed on virions in fusion-competent forms that are likely to be metastable. Activation of the viral receptor-binding domain (RBD) via its interaction with a cell surface receptor is thought to initiate a cascade of events that lead to refolding of the Env glycoprotein into its stable fusion-active conformation. While the fusion-active conformation of the TM subunit has been described in detail for several retroviruses, little is known about the fusion-competent structure of the retroviral glycoproteins or the molecular events that mediate the transition between the two conformations. By characterizing Env chimeras between the ecotropic and amphotropic murine leukemia virus (MLV) SUs as well as a set of point mutants, we show that alterations of the conformation of the SU glycoprotein strongly elevate Env fusogenicity by disrupting the stability of the Env complex. Compensatory mutations that restored both Env stability and fusion control were also identified, allowing definition of interactions within the Env complex that maintain the stability of the native Env complex. We show that, in the receptor-unbound form, structural interactions between the N terminus of the viral RBD (NTR domain), the proline-rich region (PRR), and the distal part of the C-terminal domain of the SU subunit maintain a conformation of the glycoprotein that is fusion inhibitory. Additionally, we identified mutations that disrupt this fusion-inhibitory conformation and allow fusion activation in the absence of viral receptors, provided that receptor-activated RBD fragments are added in trans during infection. Other mutations were identified that allow fusion activation in the absence of receptors for both the viral glycoprotein and the trans-acting RBD. Finally, we found mutations of the SU that bypass in cis the requirement for the NTR domain in fusion activation. All these different mutations call for a critical role of the PRR in mediating conformational changes of the Env glycoprotein during fusion activation. Our results suggest a model of MLV Env fusion activation in which unlocking of the fusion-inhibitory conformation is initiated by receptor binding of the viral RBD, which, upon disruption of the PRR, allows the NTR domain to promote further events in Env fusion activation. This involves a second type of interaction, in cis or in trans, between the receptor-activated RBD and a median segment of the freed C-terminal domain.

* Corresponding author. Mailing address: LVRTG, ENS de Lyon, 46 Allée d'Italie, 69364 Lyon Cedex 07, France. Phone and fax: 33 472 72 87 32. E-mail: flcosset{at}ens-lyon.fr.

{dagger} Present address: Department of Biochemistry and Molecular Biology, Oregon Health Sciences University, Portland, OR 97201-3098.

Journal of Virology, October 2002, p. 9673-9685, Vol. 76, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.19.9673-9685.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Argaw, T., Figueroa, M., Salomon, D. R., Wilson, C. A. (2008). Identification of Residues outside of the Receptor Binding Domain That Influence the Infectivity and Tropism of Porcine Endogenous Retrovirus. J. Virol. 82: 7483-7491 [Abstract] [Full Text]  
  • Bertrand, P., Cote, M., Zheng, Y.-M., Albritton, L. M., Liu, S.-L. (2008). Jaagsiekte Sheep Retrovirus Utilizes a pH-Dependent Endocytosis Pathway for Entry. J. Virol. 82: 2555-2559 [Abstract] [Full Text]  
  • Murphy, S. L., Chung-Landers, M., Honczarenko, M., Gaulton, G. N. (2006). Linkage of Reduced Receptor Affinity and Superinfection to Pathogenesis of TR1.3 Murine Leukemia Virus. J. Virol. 80: 4601-4609 [Abstract] [Full Text]  
  • Cheng, H. H., Anderson, M. M., Hankenson, F. C., Johnston, L., Kotwaliwale, C. V., Overbaugh, J. (2006). Envelope Determinants for Dual-Receptor Specificity in Feline Leukemia Virus Subgroup A and T Variants. J. Virol. 80: 1619-1628 [Abstract] [Full Text]  
  • Chang, K. W., Barsov, E. V., Ferris, A. L., Hughes, S. H. (2005). Mutations of a Residue within the Polyproline-Rich Region of Env Alter the Replication Rate and Level of Cytopathic Effects in Chimeric Avian Retroviral Vectors. J. Virol. 79: 10258-10267 [Abstract] [Full Text]  
  • Farrell, K. B., Eiden, M. V. (2005). Dissection of Gammaretroviral Receptor Function by Using Type III Phosphate Transporters as Models. J. Virol. 79: 9332-9336 [Abstract] [Full Text]  
  • Wallin, M., Ekstrom, M., Garoff, H. (2005). The Fusion-Controlling Disulfide Bond Isomerase in Retrovirus Env Is Triggered by Protein Destabilization. J. Virol. 79: 1678-1685 [Abstract] [Full Text]  
  • Lavillette, D., Kabat, D. (2004). Porcine Endogenous Retroviruses Infect Cells Lacking Cognate Receptors by an Alternative Pathway: Implications for Retrovirus Evolution and Xenotransplantation. J. Virol. 78: 8868-8877 [Abstract] [Full Text]  
  • O'Reilly, L., Roth, M. J. (2003). G541R within the 4070A TM Protein Regulates Fusion in Murine Leukemia Viruses. J. Virol. 77: 12011-12021 [Abstract] [Full Text]  
  • Hotzel, I., Cheevers, W. P. (2003). Caprine Arthritis-Encephalitis Virus Envelope Surface Glycoprotein Regions Interacting with the Transmembrane Glycoprotein: Structural and Functional Parallels with Human Immunodeficiency Virus Type 1 gp120. J. Virol. 77: 11578-11587 [Abstract] [Full Text]  
  • Bartosch, B., Vitelli, A., Granier, C., Goujon, C., Dubuisson, J., Pascale, S., Scarselli, E., Cortese, R., Nicosia, A., Cosset, F.-L. (2003). Cell Entry of Hepatitis C Virus Requires a Set of Co-receptors That Include the CD81 Tetraspanin and the SR-B1 Scavenger Receptor. J. Biol. Chem. 278: 41624-41630 [Abstract] [Full Text]  
  • Lu, C.-W., Roth, M. J. (2003). Role of the Mutation Q252R in Activating Membrane Fusion in the Murine Leukemia Virus Surface Envelope Protein. J. Virol. 77: 10841-10849 [Abstract] [Full Text]  
  • Burkhart, M. D., Kayman, S. C., He, Y., Pinter, A. (2003). Distinct Mechanisms of Neutralization by Monoclonal Antibodies Specific for Sites in the N-Terminal or C-Terminal Domain of Murine Leukemia Virus SU. J. Virol. 77: 3993-4003 [Abstract] [Full Text]  
  • Wensel, D. L., Li, W., Cunningham, J. M. (2003). A Virus-Virus Interaction Circumvents the Virus Receptor Requirement for Infection by Pathogenic Retroviruses. J. Virol. 77: 3460-3469 [Abstract] [Full Text]  
  • Barnett, A. L., Wensel, D. L., Li, W., Fass, D., Cunningham, J. M. (2003). Structure and Mechanism of a Coreceptor for Infection by a Pathogenic Feline Retrovirus. J. Virol. 77: 2717-2729 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»