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J. Biol. Chem., Vol. 281, Issue 9, 5829-5836, March 3, 2006

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The Endonuclease Domain of Bacteriophage Terminases Belongs to the Resolvase/Integrase/Ribonuclease H Superfamily

A BIOINFORMATICS ANALYSIS VALIDATED BY A FUNCTIONAL STUDY ON BACTERIOPHAGE T5^*

Luc Ponchon¹, Pascale Boulanger, Gilles Labesse, and Lucienne Letellier²

From the Institut de Biochimie et Biophysique Moléculaire et Cellulaire, Unite Mixte de Recherche CNRS 8619, Btiment 430, Université de Paris-Sud, 91405 Orsay, France and Centre de Biochimie Structurale, INSERM U554, CNRS UMR5048, Université Montpellier I, 29 Rue de Navacelles, 34060 Montpellier, France

Bacteriophage terminases are essential molecular motors involved in the encapsidation of viral DNA. They are hetero-multimers whose large subunit encodes both ATPase and endonuclease activities. Although the ATPase domain is well characterized from sequence and functional analysis, the C-terminal region remains poorly defined. We describe sequence-structure comparisons of the endonuclease region of various bacteriophages that revealed new sequence similarities shared by this region and the Holliday junction resolvase RuvC and to a lesser extent the HIV integrase and the ribonuclease H. Extensive sequence comparison and motif refinement led to a common signature of terminases and resolvases with three conserved acidic residues engaged in catalytic activity. Sequence analyses were validated by in vivo and in vitro functional assays showing that the nuclease activity of the endonuclease domain of bacteriophage T5 terminase was abolished by mutation of any of the three predicted catalytic aspartates. Overall, these data suggest that the endonuclease domains of terminases operate autonomously and that they adopt a fold similar to that of resolvases and share the same divalent cation-dependent enzymatic mechanism.

Received for publication, November 2, 2005 , and in revised form, December 22, 2005.

^* This work was supported in part by the CNRS program "Dynamique et Réactivité des Assemblages Biologiques." 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 Recipient of a postdoctoral CNRS fellowship. Present address: Université René Descartes Paris V, UMR CNRS 8015, Faculté de Pharmacie, 06 Paris, France.

² To whom correspondence should be addressed. Tel.: 33-1-69-15-64-29; Fax: 33-1-69-15-47-27; E-mail: lucienne.letellier{at}biomemb.u-psud.fr.

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