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J. Biol. Chem., Vol. 283, Issue 4, 2439-2453, January 25, 2008

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The SH3-like Domain Switches Its Interaction Partners to Modulate the Repression Activity of Mycobacterial Iron-dependent Transcription Regulator in Response to Metal Ion Fluctuations^*

Chong Liu, Kai Mao, Meng Zhang, Zhaogang Sun^¶, Weizhe Hong¹, Chuanyou Li^¶, Bo Peng^||, and Zengyi Chang^**2

From the Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, the School of Life Sciences, Peking University, Beijing 100871, the ^¶Department of Bacteriology and Immunology, Beijing Tuberculosis and Thoratic Tumor Research Institute, Beijing 101149, the ^||College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei Province 430074, and ^**The Center for Protein Science and The National Laboratory of Protein Engineering and Plant Genetic Engineering, Peking University, Beijing 100871, China

Iron-dependent regulator (IdeR), a metal ion-activated pleiotropic transcription factor, plays a critical role in maintaining the intracellular iron homeostasis in Mycobacteria, which is important for the normal growth of the cells. This study was initially performed in an attempt to elucidate all potential interactions between the various domains of IdeR that occur in living mycobacterial cells. This led to a hitherto unidentified self-association for the SH3-like domain of IdeR. Further studies demonstrate that the SH3-like domain interacts with different partners in the dimeric forms of IdeR depending on the levels of metal ions in the environment: it undergoes inter-subunit self-association in the metal-free DNA-non-binding form, but interacts with the N-terminal domain in the metal-bound DNA-binding form in an intra-subunit manner to finely modulate the transcription repression activity of IdeR. Our more detailed mapping studies reveal that the SH3-like domain uses an overlapping surface to participate in these two interactions, which therefore occur in a mutually exclusive fashion. This novel mechanism would allow an effective and cooperative interconversion between the two functional forms of IdeR. Our data also demonstrate that a disturbance of the interactions involving the SH3-like domain impairs the transcription repression activity of IdeR and delays the growth of mycobacterial cells.

Received for publication, August 8, 2007 , and in revised form, November 26, 2007.

^* This work was supported by grants from the National Key Basic Research Foundation of China (Grants 2006CB806508 and 2006CB910300) and National Science Foundation of China (Grants 30570355 and 30670022). 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. S1 and S2 and Tables S1 and S2.

¹ Present address: Dept. of Biological Sciences, Stanford University, Stanford, CA 94305.

² To whom correspondence should be addressed. Tel.: 86-10-6275-8822; Fax: 86-10-6275-1526; E-mail: changzy{at}pku.edu.cn.

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