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J. Biol. Chem., Vol. 280, Issue 31, 28591-28600, August 5, 2005

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Crystal Structure of Phosphorylcholine Esterase Domain of the Virulence Factor Choline-binding Protein E from Streptococcus pneumoniae

NEW STRUCTURAL FEATURES AMONG THE METALLO--LACTAMASE SUPERFAMILY^*

Gianpiero Garau, David Lemaire¶, Thierry Vernet||, Otto Dideberg, and Anne Marie Di Guilmi||**

From the Laboratoire de Cristallographie Macromoléculaire, ^¶Laboratoire de Spectrométrie de Masse des Protéines, and ^||Laboratoire d'Ingénierie des Macromolécules, Institut de Biologie Structurale Jean-Pierre Ebel (CEA-CNRS UMR 5075-UJF), 41 Rue Jules Horowitz 38027, Grenoble Cedex 1, France

Streptococcus pneumoniae is the worldwide leading cause of deaths from invasive infections such as pneumoniae, sepsis, and meningitidis in children and the elderly. Nasopharyngeal colonization, which plays a key role in the development of pneumococcal disease, is highly dependent on a family of surface-exposed proteins, the choline-binding proteins (CBPs). Here we report the crystal structure of phosphorylcholine esterase (Pce), the catalytic domain of choline-binding protein E (CBPE), which has been shown to be crucial for host/pathogen interaction processes. The unexpected features of the Pce active site reveal that this enzyme is unique among the large family of hydrolases harboring the metallo--lactamase fold. The orientation and calcium stabilization features of an elongated loop, which lies on top of the active site, suggest that the cleft may be rearranged. Furthermore, the structure of Pce complexed with phosphorylcholine, together with the characterization of the enzymatic role played by two iron ions located in the active site allow us to propose a reaction mechanism reminiscent of that of purple acid phosphatase. This mechanism is supported by site-directed mutagenesis experiments. Finally, the interactions of the choline binding domain and the Pce region of CBPE with chains of teichoic acids have been modeled. The ensemble of our biochemical and structural results provide an initial understanding of the function of CBPE.

Received for publication, March 14, 2005 , and in revised form, May 19, 2005.

The atomic coordinates and structure factors (code 1WRA) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* 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.

Recipient of a postdoctoral fellowship from the European Union in the frame of the MEBEL contract (HPRN-CT-2002-00264).

^** To whom correspondence should be addressed. Tel.: 33-0-4-38-78-56-34; Fax: 33-0-4-38-78-54-94; E-mail: diguilmi{at}ibs.fr.

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