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Journal of Virology, November 2002, p. 10861-10872, Vol. 76, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.21.10861-10872.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Envelope Proteins Containing Single Amino Acid Substitutions Support a Structural Model of the Receptor-Binding Domain of Bovine Leukemia Virus Surface Protein

Elizabeth R. Johnston,1,{dagger} Lorraine M. Albritton,2 and Kathryn Radke1*

Department of Animal Science and Graduate Group in Biochemistry and Molecular Biology, University of California, Davis, California 95616,1 Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 381632

Received 25 March 2002/ Accepted 24 July 2002

Functional domains of the strikingly conserved envelope (Env) glycoproteins of bovine leukemia virus (BLV) and its close relative, human T-cell leukemia virus type 1 (HTLV-1), are still being defined. We have used BLV Env protein variants to gain insights into the structure and function of this important determinant of viral infectivity. Each of 23 different single amino acid variants found in cDNA clones of env transcripts present after short-term culture of peripheral blood mononuclear cells from BLV-infected sheep was expressed in COS-1 cells and tested for the ability to mediate cell fusion and to be cleaved to surface (SU) and transmembrane (TM) protein subunits. Of 11 Env variants that failed to induce syncytia or did so poorly, 7 contained changes in amino acids identical or chemically conserved in the HTLV-1 Env protein. These seven included the four variants that showed aberrant proteolytic cleavage and poor cell surface expression, underscoring their importance for Env structure. Ten of 12 variants that retained wild-type syncytium-inducing ability clustered in the N-terminal half of BLV SU, which forms the putative receptor-binding domain (RBD). Several variants in the RBD showed evidence of subtle misfolding, as judged by reduced binding to monoclonal antibodies recognizing conformational epitopes F, G, and H formed by the N terminus of SU. We modeled the BLV RBD by aligning putative structural elements with known elements of the ecotropic Friend murine leukemia virus RBD monomer. All the variant RBD residues but one are exposed on the surface of this BLV model. These variants as well as function-altering, antibody-reactive residues defined by other investigators group on one face of the molecular model. They are strikingly absent from the opposite face, implying that it is likely to face inward in Env complexes. This surface might interact with the C-terminal domain of SU or with an adjacent monomer in the Env oligomer. This location suggests an orientation for the monomer of ecotropic Friend murine leukemia virus RBD.

* Corresponding author. Mailing address: Department of Animal Science, University of California, One Shields Ave., Davis, CA 95616-8521. Phone: (530) 752-9025. Fax: (530) 752-0175. E-mail: KLRadke{at}ucdavis.edu.

{dagger} Present address: Division of Infectious Diseases, School of Medicine, Stanford University, Stanford, CA 94305-5107.

Journal of Virology, November 2002, p. 10861-10872, Vol. 76, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.21.10861-10872.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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