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Journal of Virology, December 1998, p. 9955-9965, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

A Proline-Rich Motif Downstream of the Receptor Binding Domain Modulates Conformation and Fusogenicity of Murine Retroviral Envelopes

Dimitri Lavillette,1 Marielle Maurice,1 Catherine Roche,1 Stephen J. Russell,2 Marc Sitbon,3 and François-Loïc Cosset1,*

Centre de Génétique Moléculaire et Cellulaire, CNRS UMR 5534, UCB Lyon-I, 69622 Villeurbanne Cedex,1 and Institut de Génétique Moléculaire, CNRS UMR 5535, and Université Montpellier II, Montpellier,3 France, and Cambridge Centre for Protein Engineering, MRC Center, Cambridge, United Kingdom2

Received 15 July 1998/Accepted 9 September 1998

The entry of retroviruses into cells depends on receptor recognition by the viral envelope surface subunit SU followed by membrane fusion, which is thought to be mediated by a fusion peptide located at the amino terminus of the envelope transmembrane subunit TM. Several fusion determinants have been previously identified in murine leukemia virus (MLV) envelopes, but their functional interrelationships as well as the processes involved in fusion activation upon retroviral receptor recognition remain unelucidated. Despite both structural and functional similarities of their envelope glycoproteins, ecotropic and amphotropic MLVs display two different postbinding properties: (i) while amphotropic MLVs fuse the cells at neutral pH, penetration of ecotropic MLVs is relatively acid pH dependent and (ii) ecotropic envelopes are more efficient than amphotropic envelopes in inducing cell-to-cell fusion and syncytium formation. By exploiting the latter characteristic in the analysis of chimeras of ecotropic and amphotropic MLV envelopes, we show here that substitution of the ecotropic MLV proline-rich region (PRR), located in the SU between the amino-terminal receptor binding domain and the TM-interacting SU carboxy-terminal domains, is sufficient to revert the amphotropic low-fusogenic phenotype into a high-fusogenic one. Furthermore, we have identified potential beta -turns in the PRR that control the stability of SU-TM associations as well as the thresholds required to trigger either cell-to-cell or virus-to-cell fusion. These data, demonstrating that the PRR functions as a signal which induces envelope conformational changes leading to fusion, have enabled us to derive envelopes which can infect cells harboring low levels of available amphotropic receptors.

* Corresponding author. Present address: LVRTG, INSERM U412, ENS de Lyon, 46 allée d'Italie, 69367 Lyon Cedex 07, France. Phone and Fax: 33 4 72 72 87 32. E-mail: Francois_Loic.Cosset{at}ens-lyon.fr.

Journal of Virology, December 1998, p. 9955-9965, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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