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J. Biol. Chem., Vol. 282, Issue 43, 31534-31541, October 26, 2007

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Structural and Functional Studies of the Abundant Tegument Protein ORF52 from Murine Gammaherpesvirus 68^*

Jordi Benach, Lili Wang¹, Yang Chen¹, Chi Kent Ho^¶, Shaoying Lee^||, Jayaraman Seetharaman, Rong Xiao^¶, Thomas B. Acton^¶, Gaetano T. Montelione^¶, Hongyu Deng^||, Ren Sun^**2, and Liang Tong³

From the Department of Biological Sciences, Northeast Structural Genomics Consortium, Columbia University, New York, New York 10027, the Center for Infection and Immunity, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China, the ^¶Center for Advanced Biotechnology and Medicine and Department of Molecular Biology and Biochemistry, Northeast Structural Genomics Consortium, Rutgers University, Piscataway, New Jersey 08854, and the ^||School of Dentistry and the ^**Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California 90095

The tegument is a layer of proteins between the nucleocapsid and the envelope of herpesviruses. The functions of most tegument proteins are still poorly understood. In murine gammaherpesvirus 68, ORF52 is an abundant tegument protein of 135 residues that is required for the assembly and release of infectious virus particles. To help understand the molecular basis for the function of this protein, we have determined its crystal structure at 2.1 Å resolution. The structure reveals a dimeric association of this protein. Interestingly, an N-terminal -helix that assumes different conformation in the two monomers of the dimer mediates the formation of an asymmetrical tetramer and contains many highly conserved residues. Structural and sequence analyses suggest that this helix is more likely involved in interactions with other components of the tegument or nucleocapsid of the virus and that ORF52 functions as a symmetrical dimer. The asymmetrical tetramer of ORF52 may be a "latent" form of the protein, when it is not involved in virion assembly. The self-association of ORF52 has been confirmed by co-immunoprecipitation and fluorescence resonance energy transfer experiments. Deletion of the N-terminal -helix, as well as mutation of the conserved Arg⁹⁵ residue, abolished the function of ORF52. The results of the functional studies are fully consistent with the structural observations and indicate that the N-terminal -helix is a crucial site of interaction for ORF52.

Received for publication, July 10, 2007

The atomic coordinates and structure factors (code 2OA5) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by Grant U54 GM074958 from the Protein Structure Initiative of the NIGMS, National Institutes of Health, by National Institutes of Health Grant R01 DE015752, and by National Protein Project Grant 2006CB910901. 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 These authors contributed equally to this work.

² To whom correspondence may be addressed. Tel.: 310-794-5557; Fax: 310-794-5123; E-mail: rsun{at}mednet.ucla.edu. ³ To whom correspondence may be addressed. Tel.: 212-854-5203; Fax: 212-865-8246; E-mail: ltong{at}columbia.edu.

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