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Journal of Virology, April 2000, p. 3642-3649, Vol. 74, No. 8
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Identification of Amino Acid Residues in CD81 Critical for Interaction with Hepatitis C Virus Envelope Glycoprotein E2

Adrian Higginbottom,1 Elizabeth R. Quinn,2 Chiung-Chi Kuo,2 Mike Flint,3 Louise H. Wilson,3 Elisabetta Bianchi,4 Alfredo Nicosia,4 Peter N. Monk,1 Jane A. McKeating,3,dagger and Shoshana Levy2,*

Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2UH,1 and School of Animal and Microbial Sciences, University of Reading, Reading RG6 6AJ,3 United Kingdom; Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford, California 943052; and IRBM, 00040 Pomezia, Rome, Italy4

Received 4 October 1999/Accepted 24 January 2000

Human CD81 has been previously identified as the putative receptor for the hepatitis C virus envelope glycoprotein E2. The large extracellular loop (LEL) of human CD81 differs in four amino acid residues from that of the African green monkey (AGM), which does not bind E2. We mutated each of the four positions in human CD81 to the corresponding AGM residues and expressed them as soluble fusion LEL proteins in bacteria or as complete membrane proteins in mammalian cells. We found human amino acid 186 to be critical for the interaction with the viral envelope glycoprotein. This residue was also important for binding of certain anti-CD81 monoclonal antibodies. Mutating residues 188 and 196 did not affect E2 or antibody binding. Interestingly, mutation of residue 163 increased both E2 and antibody binding, suggesting that this amino acid contributes to the tertiary structure of CD81 and its ligand-binding ability. These observations have implications for the design of soluble high-affinity molecules that could target the CD81-E2 interaction site(s).

* Corresponding author. Mailing address: Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford, CA 94305. Phone: (650) 725-6425. Fax: (650) 725-1420. E-mail: levy{at}cmgm.stanford.edu.

dagger Present address: Central Research, Pfizer Ltd., Sandwich, Kent CT13 9NJ, United Kingdom.

Journal of Virology, April 2000, p. 3642-3649, Vol. 74, No. 8
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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