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Journal of Virology, April 1999, p. 3087-3094, Vol. 73, No. 4
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Substitutions in the Receptor-Binding Domain of the Avian Sarcoma and Leukosis Virus Envelope Uncouple Receptor-Triggered Structural Rearrangements in the Surface and Transmembrane Subunits

Rachel Damico, Lijun Rong,dagger and Paul Bates*

Department of Microbiology, Graduate Program in Cellular and Molecular Biology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6076

Received 10 September 1998/Accepted 23 December 1998

The retrovirus avian sarcoma and leukosis virus (ASLV) enters cells via pH-independent membrane fusion. This reaction is catalyzed by the viral glycoprotein Env, composed of a membrane-distal subunit, SU, and a membrane-anchored subunit, TM. Previous mutational analysis of a variable region, central within the SU subunit, indicates that this region constitutes part of the receptor-binding domain for subgroup A envelope (EnvA) and furthermore that basic residues (R210, R213, R223, R224, and K227) within this region are critical determinants of efficient ASLV infection. Substitutions of these basic residues exert effects on both receptor binding and postbinding events in EnvA-mediated entry. In this study, we performed biochemical analysis of the EnvA protein from three of the receptor-binding domain mutants (R213A/K227A, R213A/R223A/R224A, and R213S) to define the role of this domain in early molecular events in the entry pathway. Protease sensitivity assays demonstrated that receptor binding was sufficient to trigger conformational changes in the SU subunit of mutants R213A/K227A and R213S similar to those in the wild-type EnvA, while R213A/R223A/R224A was constitutively sensitive to protease. In contrast, all three receptor-binding domain mutants disrupted receptor-triggered conversion of EnvA to an active, membrane-binding conformation as assessed by liposome flotation assays. Our results demonstrate that mutations in the receptor-binding site can dissociate receptor-triggered conformational changes in the SU subunit from membrane binding. Furthermore, they suggest that communication between the receptor-binding subunit, SU, and the fusogenic subunit, TM, is crucial for efficient activation of the fusogenic state of EnvA. Analysis of these mutants continues earlier observations that binding to the cellular receptor provides the trigger for efficient activation of this pH-independent viral envelope protein.

* Corresponding author. Mailing address: Department of Microbiology, Graduate Program in Cellular and Molecular Biology, School of Medicine, University of Pennsylvania, 3610 Hamilton Walk, Philadelphia, PA 19104-6076. Phone: (215) 573-3509. Fax: (215) 573-4184. E-mail: pbates{at}mail.med.upenn.edu.

dagger Present address: Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612-7344.

Journal of Virology, April 1999, p. 3087-3094, Vol. 73, No. 4
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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