HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 46, 33681-33690, November 16, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/46/33681    most recent M706863200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kimura, M. Articles by Yamamoto, M. Search for Related Content PubMed PubMed Citation Articles by Kimura, M. Articles by Yamamoto, M. Social Bookmarking                      What's this?

Molecular Basis Distinguishing the DNA Binding Profile of Nrf2-Maf Heterodimer from That of Maf Homodimer^*

Momoko Kimura, Tae Yamamoto, Jianyong Zhang, Ken Itoh^¶, Motoki Kyo^||, Terue Kamiya^||, Hiroyuki Aburatani^**, Fumiki Katsuoka, Hirofumi Kurokawa, Toshiyuki Tanaka, Hozumi Motohashi^¶¶, and Masayuki Yamamoto^¶¶1

From the Graduate School of Comprehensive Human Sciences and Center for Tsukuba Advanced Research Alliance and Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8572, Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, ^¶Department of Stress Response Science, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, ^||TOYOBO Co. Ltd. Biotechnology Frontier Project, 10-24 Toyo-Cho, Tsuruga, 914-0047, ^**Research Center for Advance Science and Technology, University of Tokyo, Tokyo 153-8904, Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Katahira 2-1-1, Aoba-ku, Sendai 980-8577, and ^¶¶Environmental Response Project, Exploratory Research for Advanced Technology-Japan Science and Technology Corp. (ERATO-JST), Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan

Nrf2-small Maf heterodimer activates the transcription of many cytoprotective genes through the antioxidant response element and serves as a key factor in xenobiotic and oxidative stress responses. Our surface plasmon resonance-microarray binding analysis revealed that both Nrf2-MafG heterodimer and MafG homodimer bind to the consensus Maf recognition element with high affinity but bind differentially to the suboptimal binding sequences degenerated from the consensus. We examined the molecular basis distinguishing the binding profile of Nrf2-MafG heterodimer from that of MafG homodimer and found that the Ala-502 residue in the basic region of Nrf2 is a critical determinant of its binding specificity. In Maf proteins, a tyrosine resides in the position corresponding to Ala-502 in Nrf2. We prepared a mutant Nrf2 molecule in which Ala-502 was replaced with tyrosine. In surface plasmon resonance-microarray analysis, heterodimer of Nrf2(A502Y) and MafG displayed a binding specificity similar to that of MafG homodimer. The target genes activated by mutant Nrf2(A502Y)-small Maf heterodimer were largely different, albeit with some overlap, from those activated by wild-type Nrf2-small Maf, indicating that the array of target genes regulated by Nrf2-small Maf heterodimer differs substantially from that regulated by Maf homodimer in vivo. These results suggest that the distinct DNA binding profile of Nrf2-Maf heterodimer is biologically significant for Nrf2 to function as a key regulator of cytoprotective genes. Our contention is supported that the differential DNA binding specificity between Maf homodimers and Nrf2-Maf heterodimers establishes the differential gene regulation by these dimer-forming transcription factors.

Received for publication, August 17, 2007 , and in revised form, September 17, 2007.

^* This work was supported in part by grants from ERATO-JST (to M. Y.), a grant-in-aid for Creative Scientific Research (to M. Y.), for Scientific Research on Priority Areas (to H. M. and M. Y.), for Scientific Research (H. M. and M. Y.), and for Exploratory Research (to M. Y.) from the Ministry of Education, Science, Sports and Culture, Naito foundation (to M. Y.), by The Cell Science Research Foundation (H. M.), and by Gonryo Medical Foundation (H. M.). 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 Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan. Tel.: 81-22-717-8088; Fax: 81-22-717-8090; E-mail: hozumim{at}mail.tains.tohoku.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?