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J. Biol. Chem., Vol. 283, Issue 8, 4895-4904, February 22, 2008

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The Oligomeric State of the Active BM2 Ion Channel Protein of Influenza B Virus^*

Victoria Balannik, Robert A. Lamb^¶1, and Lawrence H. Pinto²

From the Department of Neurobiology and Physiology, Department of Biochemistry, Molecular Biology and Cell Biology, and the ^¶Howard Hughes Medical Institute, Northwestern University, Evanston, Illinois 60208-3500

Influenza A virus and influenza B virus particles both contain small integral membrane proteins (A/M2 and BM2, respectively) that function as a pH-sensitive proton channel and are essential for virus replication. The mechanism of action of the M2 channels is a subject of scientific interest particularly as A/M2 channel was shown to be a target for the action of the antiviral drug amantadine. Unfortunately, an inhibitor of the BM2 channel activity is not known. Thus, knowledge of the structural and functional properties of the BM2 channel is essential for the development of potent antiviral drugs. The characterization of the oligomeric state of the BM2 channel is an essential first step in the understanding of channel function. Here we describe determination of the stoichiometry of the BM2 proton channel by utilizing three different approaches. 1) We demonstrated that BM2 monomers can be chemically cross-linked to yield species consistent with dimers, trimers, and tetramers. 2) We studied electrophysiological and biochemical properties of mixed oligomers consisting of wild-type and mutated BM2 subunits and related these data to predicted binomial distribution models. 3) We used fluorescence resonance energy transfer (FRET) in combination with biochemical measurements to estimate the relationships between BM2 channel subunits expressed in the plasma membrane. Our experimental data are consistent with a tetrameric structure of the BM2 channel. Finally, we demonstrated that BM2 transmembrane domain is responsible for the channel oligomerization.

Received for publication, November 16, 2007 , and in revised form, December 10, 2007.

^* This work was supported by National Institutes of Health Research Grant AI-57363 (to L. H. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ An Investigator of the Howard Hughes Medical Institute.

² To whom correspondence should be addressed: Dept. of Neurobiology and Physiology, Hogan Hall, 2205 Tech Drive, Northwestern University, Evanston, IL 60208-3500. Tel.: 847-491-7915; Fax: 847-491-5211; E-mail: larry-pinto{at}northwestern.edu.

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				X. Jing, C. Ma, Y. Ohigashi, F. A. Oliveira, T. S. Jardetzky, L. H. Pinto, and R. A. Lamb Functional studies indicate amantadine binds to the pore of the influenza A virus M2 proton-selective ion channel PNAS, August 5, 2008; 105(31): 10967 - 10972. [Abstract] [Full Text] [PDF]

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