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Molecular and Cellular Biology, November 2007, p. 7511-7521, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00753-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Different Electrostatic Potentials Define ETGE and DLG Motifs as Hinge and Latch in Oxidative Stress Response{triangledown}

Kit I. Tong,1,{dagger} Balasundaram Padmanabhan,2,{dagger} Akira Kobayashi,1 Chengwei Shang,2 Yosuke Hirotsu,1 Shigeyuki Yokoyama,2,3* and Masayuki Yamamoto1,4*

Graduate School of Comprehensive Human Sciences, Center for TARA, and JST-ERATO Environmental Response Project, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577,1 Protein Research Group, Genomic Sciences Center, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045,2 Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo 113-0033,3 Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan4

Received 30 April 2007/ Returned for modification 20 June 2007/ Accepted 21 August 2007

Nrf2 is the regulator of the oxidative/electrophilic stress response. Its turnover is maintained by Keap1-mediated proteasomal degradation via a two-site substrate recognition mechanism in which two Nrf2-Keap1 binding sites form a hinge and latch. The E3 ligase adaptor Keap1 recognizes Nrf2 through its conserved ETGE and DLG motifs. In this study, we examined how the ETGE and DLG motifs bind to Keap1 in a very similar fashion but with different binding affinities by comparing the crystal complex of a Keap1-DC domain-DLG peptide with that of a Keap1-DC domain-ETGE peptide. We found that these two motifs interact with the same basic surface of either Keap1-DC domain of the Keap1 homodimer. The DLG motif works to correctly position the lysines within the Nrf2 Neh2 domain for efficient ubiquitination. Together with the results from calorimetric and functional studies, we conclude that different electrostatic potentials primarily define the ETGE and DLG motifs as a hinge and latch that senses the oxidative/electrophilic stress.

* Corresponding author. Mailing address for Shigeyuki Yokoyama: Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. Phone: 81-45-503-9196. Fax: 81-45-503-9195. E-mail: yokoyama{at}biochem.s.u-tokyo.ac.jp. Mailing address for Masayuki Yamamoto: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan. Phone: 81-22-717-8084. Fax: 81-22-717-8090. E-mail: masi{at}mail.tains.tohoku.ac.jp

{triangledown} Published ahead of print on 4 September 2007.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, November 2007, p. 7511-7521, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00753-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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