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Journal of Virology, August 2002, p. 7683-7693, Vol. 76, No. 15
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.15.7683-7693.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Reassessing the Role of Region A in Pit1-Mediated Viral Entry

Karen B. Farrell, Jill L. Russ, Ravi K. Murthy, and Maribeth V. Eiden*

Unit on Molecular Virology, Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, Bethesda, Maryland 20892

Received 6 March 2002/ Accepted 23 April 2002

The mammalian gammaretroviruses gibbon ape leukemia virus (GALV) and feline leukemia virus subgroup B (FeLV-B) can use the same receptor, Pit1, to infect human cells. A highly polymorphic nine-residue sequence within Pit1, designated region A, has been proposed as the virus binding site, because mutations in this region abolish Pit1-mediated cellular infection by GALV and FeLV-B. However, a direct correlation between region A mutations deleterious for infection and loss of virus binding has not been established. We report that cells expressing a Pit1 protein harboring mutations in region A that abolish receptor function retain the ability to bind virus, indicating that Pit1 region A is not the virus binding site. Furthermore, we have now identified a second region in Pit1, comprising residues 232 to 260 (region B), that is required for both viral entry and virus binding. Epitope-tagged Pit1 proteins were used to demonstrate that mutations in region B result in improper orientation of Pit1 in the cell membrane. Compensatory mutations in region A can restore proper orientation and full receptor function to these region B mutants. Based on these results, we propose that region A of Pit1 confers competence for viral entry by influencing the topology of the authentic binding site in the membrane and hence its accessibility to a viral envelope protein. Based on glycosylation studies and results obtained by using N- and C-terminal epitope-tagged Pit1, region A and region B mutants, and the transmembrane helices predicted with the PHD PredictProtein algorithm, we propose a new Pit1 topology model.

* Corresponding author. Mailing address: Building 36, Room 2A11, Unit on Molecular Virology, Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, 36 Convent Dr., MSC 4068, Bethesda, MD 20892. Phone: (301) 402-1641. Fax: (301) 402-5358. E-mail: m_eiden{at}codon.nih.gov.

Journal of Virology, August 2002, p. 7683-7693, Vol. 76, No. 15
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.15.7683-7693.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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