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J. Biol. Chem., Vol. 282, Issue 27, 19606-19618, July 6, 2007

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Molecular and Structural Characterization of the PezAT Chromosomal Toxin-Antitoxin System of the Human Pathogen Streptococcus pneumoniae^*

Seok Kooi Khoo¹, Bernhard Loll¹, Wai Ting Chan, Robert L. Shoeman, Lena Ngoo, Chew Chieng Yeo², and Anton Meinhart³

From the Department of Biomolecular Mechanisms, Max-Planck-Institute for Medical Research, 69120 Heidelberg, Germany and the Department of Biotechnology, Malaysia University of Science and Technology, 47301 Petaling Jaya, Malaysia

The chromosomal pezT gene of the Gram-positive pathogen Streptococcus pneumoniae encodes a protein that is homologous to the zeta toxin of the Streptococcus pyogenes plasmid pSM19035-encoded epsilon-zeta toxin-antitoxin system. Overexpression of pezT in Escherichia coli led to severe growth inhibition from which the bacteria recovered 3 h after induction of expression. The toxicity of PezT was counteracted by PezA, which is encoded immediately upstream of pezT and shares weak sequence similarities in the C-terminal region with the epsilon antitoxin. The pezAT genes form a bicistronic operon that is co-transcribed from a ⁷⁰-like promoter upstream of pezA and is negatively autoregulated with PezA functioning as a transcriptional repressor and PezT as a co-repressor. Both PezA and the non-toxic PezA₂PezT₂ protein complex bind to a palindrome sequence that overlaps the promoter. This differs from the epsilon-zeta system in which epsilon functions solely as the antitoxin and transcriptional regulation is carried out by another protein designated omega. Results from site-directed mutagenesis experiments demonstrated that the toxicity of PezT is dependent on a highly conserved phosphoryltransferase active site and an ATP/GTP nucleotide binding site. In the PezA₂PezT₂ complex, PezA neutralizes the toxicity of PezT by blocking the nucleotide binding site through steric hindrance.

Received for publication, February 27, 2007 , and in revised form, April 23, 2007.

The atomic coordinates and structure factors (code 2P5T) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This research was supported by a SAGA/MUST/MZA-YCC/1 (M18) Grant from the Malaysian Academy of Sciences and the Ministry of Science, Technology and Innovation (to C. C. Y.). 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 Fig. S1 and Tables S1 and S2.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed. Tel.: 60-3-7880-1777; Fax: 60-3-7880-1762; E-mail: ccyeo{at}must.edu.my. ³ To whom correspondence may be addressed. Tel.: 49-6221-486-505; Fax: 49-6221-486-585; E-mail: Anton.Meinhart{at}mpimf-heidelberg.mpg.de.

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