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Journal of Virology, November 2002, p. 11551-11560, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11551-11560.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

LMP-1's Transmembrane Domains Encode Multiple Functions Required for LMP-1's Efficient Signaling

Ajamete Kaykas,{dagger} Kathleen Worringer,{ddagger} and Bill Sugden*

McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Wisconsin 53706-1599

Received 19 April 2002/ Accepted 14 August 2002

The latent membrane protein-1 (LMP-1) of Epstein-Barr virus (EBV) contributes to the proliferation of infected B lymphocytes by signaling through its binding to cellular signaling molecules. It apparently mimics members of the tumor necrosis factor receptor family, in particular, CD40, by binding a similar set of cellular molecules as does CD40. LMP-1 differs dramatically in its structure from CD40. LMP-1 has six membrane-spanning domains as opposed to CD40's one. LMP-1 also differs from CD40 in its apparent independence of a ligand for its signaling. We have examined the role of LMP-1's membrane-spanning domains in its signaling. Their substitution with six membrane-spanning domains from the LMP-2A protein of EBV yields a derivative which neither coimmunoprecipitates with LMP-1 nor signals to increase the activity of NF-{kappa}B as does wild-type LMP-1. These observations indicate that LMP-1 has specific sequences in its membrane-spanning domains required for these activities. LMP-1's first and sixth membrane-spanning domains have multiple leucine residues potentially similar to leucine-heptad motifs that can mediate protein-protein interactions in membranes (Gurezka et al., J. Biol. Chem. 274:9265-9270, 1999). Substitution of seven leucines in LMP-1's sixth membrane-spanning domain has no effect on its function, whereas similar substitutions in its first membrane-spanning domain yielded a derivative which aggregates as does wild-type LMP-1 but has only 3% of wild-type's ability to signal through NF-{kappa}B. Importantly, this derivative complements a mutant of LMP-1 with wild-type membrane-spanning domains but no carboxy-terminal signaling domain. These findings together indicate that the membrane-spanning domains of LMP-1 contribute multiple functions to its signaling.

* Corresponding author. Mailing address: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706. Phone: (608) 262-6697. Fax: (608) 262-2824. E-mail: sugden{at}oncology.wisc.edu.

{dagger} Present address: HHMI/Pharmacology, University of Washington-Seattle, Seattle, WA 98195.

{ddagger} Present address: Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA 94143.

Journal of Virology, November 2002, p. 11551-11560, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11551-11560.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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