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PROTEIN STRUCTURE REPORT

Crystal structures and proposed structural/functional classification of three protozoan proteins from the isochorismatase superfamily

¹ Biomolecular Structure Center, Department of Biochemistry, ² Division of Infectious Disease, and ³ Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA
⁴ Seattle Biomedical Research Institute, Seattle, Washington 98109, USA
⁵ Hauptman-Woodward Medical Research Institute, Buffalo, New York 14203, USA
⁶ Berkeley Center for Structural Biology, Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA
⁷ SSRL, Stanford University, Stanford, California 94305, USA

(RECEIVED August 15, 2005; FINAL REVISION August 15, 2005; ACCEPTED August 17, 2005)

We have determined the crystal structures of three homologous proteins from the pathogenic protozoans Leishmania donovani, Leishmania major, and Trypanosoma cruzi. We propose that these proteins represent a new subfamily within the isochorismatase superfamily (CDD classification cd004310). Their overall fold and key active site residues are structurally homologous both to the biochemically well-characterized N-carbamoylsarcosine-amidohydrolase, a cysteine hydrolase, and to the phenazine biosynthesis protein PHZD (isochorismase), an aspartyl hydrolase. All three proteins are annotated as mitochondrial-associated ribonuclease Mar1, based on a previous characterization of the homologous protein from L. tarentolae. This would constitute a new enzymatic activity for this structural superfamily, but this is not strongly supported by the observed structures. In these protozoan proteins, the extended active site is formed by inter-subunit association within a tetramer, which implies a distinct evolutionary history and substrate specificity from the previously characterized members of the isochorismatase superfamily. The characterization of the active site is supported crystallographically by the presence of an unidentified ligand bound at the active site cysteine of the T. cruzi structure.

Keywords: structural genomics; Leishmania; Trypanosoma; functional annotation; protein families; evolutionary relationships; cysteine hydrolase

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051783005.

Reprint requests to: Ethan A. Merritt, Biomolecular Structure Center M/S 357742, University of Washington, Seattle, WA 98195, USA; e-mail: merritt{at}u.washington.edu; fax: (206) 685-7002.

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