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Journal of Virology, February 2006, p. 1742-1751, Vol. 80, No. 4
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.4.1742-1751.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Comprehensive Mapping of Receptor-Functioning Domains in Feline Leukemia Virus Subgroup C Receptor FLVCR1

Jennifer K. Brown,1,2,{dagger} Claire Fung,1,2,{dagger} and Chetankumar S. Tailor1,2*

Infection, Immunity, Injury Repair Program, The Hospital for Sick Children, Toronto, Ontario M5G 1X8,1 University of Toronto, Department of Molecular and Medical Genetics, Toronto, Ontario M5G, Canada2

Received 17 August 2005/ Accepted 21 November 2005

Infection of cells by the highly anemogenic feline leukemia virus subgroup C (FeLV-C) is mediated by the heme exporter FLVCR1, a cell surface protein containing 12 potential transmembrane segments with six presumptive extracellular loops (ECLs). To identify FLVCR1 residues critical for mediating FeLV-C infection, we first independently isolated a human cDNA encoding the FLVCR2 protein that shares 52% identity to human FLVCR1, and we show that FLVCR2 does not function as a receptor for FeLV-C. Then, by generating specific hybrids between FLVCR1 and FLVCR2 and testing susceptibility of mouse cells expressing these hybrids to ß-galactosidase encoding FeLV-C, we identify FLVCR1 ECLs 1 and 6 as critical for mediating FeLV-C infection. Mouse cells expressing a hybrid protein containing FLVCR2 backbone with the ECL6 sequence from FLVCR1 were highly susceptible to FeLV-C infection. Using site-directed mutagenesis, we show that a single mutation of Asn463 in FLVCR2 ECL6 to an acidic Asp residue (a residue present in the corresponding position 487 in FLVCR1 ECL6) is sufficient to render FLVCR2 functional as an FeLV-C receptor. However, an Asp487Asn mutation in FLVCR1 ECL6 or substitution of the entire FLVCR1 ECL6 sequence for FLVCR2 ECL6 sequence does not disrupt receptor function. Subsequent substitutions show that residues within FLVCR1 ECL1 also contribute to mediating FeLV-C infection. Furthermore, our results suggest that FLVCR1 regions that mediate FeLV-C surface unit binding are distinct from ECL1 and ECL6. Our results are consistent with previous conclusions that infection of cells by gammaretroviruses involves interaction of virus with multiple receptor regions.

* Corresponding author. Mailing address: The Hospital for Sick Children, Infection, Immunity, Injury Repair Program, 555 University Avenue, Toronto, ON M5G 1X8, Canada. Phone: (416) 813-6429. Fax: (416) 813-5993. E-mail: chetankumar.tailor{at}sickkids.ca.

{dagger} J.K.B. and C.F. contributed equally to this work.

Journal of Virology, February 2006, p. 1742-1751, Vol. 80, No. 4
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.4.1742-1751.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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