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Journal of Virology, May 2005, p. 6134-6141, Vol. 79, No. 10
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.10.6134-6141.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Structural Basis for the Physiological Temperature Dependence of the Association of VP16 with the Cytoplasmic Tail of Herpes Simplex Virus Glycoprotein H

Douglas E. Kamen,^1, Sarah T. Gross,^2, Mark E. Girvin,¹ and Duncan W. Wilson^2*

Department of Biochemistry,¹ Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, New York 10461²

Received 16 July 2004/ Accepted 14 January 2005

Critical events in the life cycle of herpes simplex virus (HSV) are the binding of cytoplasmic capsids to cellular organelles and subsequent envelopment. Work from several laboratories suggests that these events occur as a result of a network of partially redundant interactions among the capsid surface, tegument components, and cytoplasmic tails of virally encoded glycoproteins. Consistent with this model, we previously showed that tegument protein VP16 can specifically interact with the cytoplasmic tail of envelope protein gH in vitro and in vivo when fused to glutathione S-transferase and to green fluorescent protein, respectively. In both instances, this association was strikingly temperature dependent: binding occurred only at 37°C and not at lower temperatures. Here we demonstrate that virally expressed full-length gH and VP16 can be coimmunoprecipitated from HSV-infected cells and that this association is also critically dependent upon the physiological temperature. To investigate the basis of this temperature requirement, we performed one- and two-dimensional nuclear magnetic resonance spectroscopy on peptides with the sequence of the gH tail. We found that the gH tail is disorganized at temperatures permissive for binding but becomes structured at lower temperatures. Furthermore, a mutated tail unable to adopt this rigid conformation binds VP16 even at 4°C. We hypothesize that the gH tail is unstructured under physiological conditions in order to maximize the number of potential tegument partners with which it may associate. Being initially disordered, the gH tail may adopt one of several induced conformations as it associates with VP16 or alternative components of the tegument, maximizing redundancy during particle assembly.

D.E.K. and S.T.G. contributed equally to the work reported in this article.

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