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J. Biol. Chem., Vol. 281, Issue 40, 30289-30298, October 6, 2006

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Structure of Francisella tularensis AcpA

PROTOTYPE OF A UNIQUE SUPERFAMILY OF ACID PHOSPHATASES AND PHOSPHOLIPASES C^*

Richard L. Felts, Thomas J. Reilly, and John J. Tanner^¶1

From the Department of Chemistry, the Department of Veterinary Pathobiology and Veterinary Medical Diagnostic Laboratory, and the ^¶Department of Biochemistry, University of Missouri, Columbia, Missouri 65211

AcpA is a respiratory burst-inhibiting acid phosphatase from the Centers for Disease Control and Prevention Category A bioterrorism agent Francisella tularensis and prototype of a superfamily of acid phosphatases and phospholipases C. We report the 1.75-Å resolution crystal structure of AcpA complexed with the inhibitor orthovanadate, which is the first structure of any F. tularensis protein and the first for any member of this superfamily. The core domain is a twisted 8-stranded -sheet flanked by three -helices on either side, with the active site located above the carboxyl-terminal edge of the -sheet. This architecture is unique among acid phosphatases and resembles that of alkaline phosphatase. Unexpectedly, the active site features a serine nucleophile and metal ion with octahedral coordination. Structure-based sequence analysis of the AcpA superfamily predicts that the hydroxyl nucleophile and metal center are also present in AcpA-like phospholipases C. These results imply a phospholipase C catalytic mechanism that is radically different from that of zinc metallophospholipases.

Received for publication, July 5, 2006 , and in revised form, August 7, 2006.

The atomic coordinates and structure factors (code 2D1G) 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 National Institutes of Health Grant U54 AI057160 to the Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research and the University of Missouri Research Board. The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, Materials Sciences Division, of the U.S. Dept. of Energy under Contract No. DE-AC03-76SF00098 at Lawrence Berkeley National Laboratory. Beamline 8.3.1 was funded by the National Science Foundation, the University of California, and Henry Wheeler. Use of the Argonne National Laboratory Structural Biology Center beamlines at the Advanced Photon Source was supported by the U.S. Dept. of Energy, Office of Energy Research, under Contract No. W-31-109-ENG-38. 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 To whom correspondence should be addressed: Dept. of Chemistry, University of Missouri, 125 Chemistry Bldg., 601 S. College Ave., Columbia, MO 65211. Tel.: 573-884-1280; Fax: 573-882-2754; E-mail: tannerjj{at}missouri.edu.

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