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J. Biol. Chem., Vol. 282, Issue 15, 11582-11589, April 13, 2007

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The Reovirus 1 Aspartic Acid Sandwich

A TRIMERIZATION MOTIF POISED FOR CONFORMATIONAL CHANGE^*

Pierre Schelling¹², Kristen M. Guglielmi^¶1, Eva Kirchner¹, Bernhard Paetzold, Terence S. Dermody^¶||3, and Thilo Stehle^¶||4

From the Interfakultäres Institut für Biochemie, Universität Tübingen, Hoppe-Seyler-Strasse 4, D-72076 Tübingen, Germany and the Department of Microbiology and Immunology, ^¶Elizabeth B. Lamb Center for Pediatric Research, and ^||Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Reovirus attachment protein 1 mediates engagement of receptors on the surface of target cells and undergoes dramatic conformational rearrangements during viral disassembly in the endocytic pathway. The 1 protein is a filamentous, trimeric molecule with a globular -barrel head domain. An unusual cluster of aspartic acid residues sandwiched between hydrophobic tyrosines is located at the 1 subunit interface. A 1.75-Å structure of the 1 head domain now reveals two water molecules at the subunit interface that are held strictly in position and interact with neighboring residues. Structural and biochemical analyses of mutants affecting the aspartic acid sandwich indicate that these residues and the corresponding chelated water molecules act as a plug to block the free flow of solvent and stabilize the trimer. This arrangement of residues at the 1 head trimer interface illustrates a new protein design motif that may confer conformational mobility during cell entry.

Received for publication, November 22, 2006 , and in revised form, January 18, 2007.

The atomic coordinates and structure factors (code 2OJ5 and 2OJ6) 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 the Swiss National Foundation (to P. S.), Public Health Service Awards T32 GM08554 (to K. M. G.) and R01 GM67853 (to T. S. D. and T. S.), and the Elizabeth B. Lamb Center for Pediatric Research. Additional support was provided by Public Health Service Awards CA68485 for the Vanderbilt Cancer Center and DK20593 for the Vanderbilt Diabetes Research and Training Center. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ These authors contributed equally to this manuscript.

² Current address: Millipore SAS, EBC, BP116, 67124 Molsheim, France.

³ To whom correspondence may be addressed: Dept. of Pediatrics, Vanderbilt University School of Medicine, 1161 21st Ave. South, Nashville, TN 37232. Tel.: 615-343-9943; Fax: 615-343-9723; E-mail: terry.dermody{at}vanderbilt.edu.

⁴ To whom correspondence may be addressed: Interfakultäres Institut für Biochemie, Universität Tübingen, Hoppe-Seyler-Str. 4, D-72076 Tübingen, Germany. Tel.: 49-7071-2973043; Fax: 49-7071-295565; E-mail: thilo.stehle{at}uni-tuebingen.de.

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