Different Electrostatic Potentials Define ETGE and DLG Motifs As Hinge and Latch in Oxidative Stress Response

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2007 Sep 6

PMID 17785452

Citations 201

Authors

Kit I Tong

Balasundaram Padmanabhan

Akira Kobayashi

Chengwei Shang

Yosuke Hirotsu

Shigeyuki Yokoyama

Masayuki Yamamoto

Affiliations

Soon will be listed here.

Abstract

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.

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