Molecular basis for the disruption of Keap1-Nrf2 interaction via Hinge & Latch mechanism

Yuta Horie, Takafumi Suzuki, Jin Inoue, Tatsuro Iso, Geoffrey Wells, Terry W. Moore, Tsunehiro Mizushima, Albena T. Dinkova-Kostova, Takuma Kasai, Takashi Kamei, Seizo Koshiba (Lead / Corresponding author), Masayuki Yamamoto (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    107 Citations (Scopus)
    148 Downloads (Pure)

    Abstract

    The Keap1-Nrf2 system is central for mammalian cytoprotection against various stresses and a drug target for disease prevention and treatment. One model for the molecular mechanisms leading to Nrf2 activation is the Hinge-Latch model, where the DLGex-binding motif of Nrf2 dissociates from Keap1 as a latch, while the ETGE motif remains attached to Keap1 as a hinge. To overcome the technical difficulties in examining the binding status of the two motifs during protein-protein interaction (PPI) simultaneously, we utilized NMR spectroscopy titration experiments. Our results revealed that latch dissociation is triggered by low-molecular-weight Keap1-Nrf2 PPI inhibitors and occurs during p62-mediated Nrf2 activation, but not by electrophilic Nrf2 inducers. This study demonstrates that Keap1 utilizes a unique Hinge-Latch mechanism for Nrf2 activation upon challenge by non-electrophilic PPI-inhibiting stimuli, and provides critical insight for the pharmacological development of next-generation Nrf2 activators targeting the Keap1-Nrf2 PPI.

    Original languageEnglish
    Article number576
    Number of pages11
    JournalCommunications Biology
    Volume4
    DOIs
    Publication statusPublished - 14 May 2021

    Keywords

    • Molecular biology
    • Solution-state NMR

    ASJC Scopus subject areas

    • General Agricultural and Biological Sciences
    • General Biochemistry,Genetics and Molecular Biology
    • Medicine (miscellaneous)

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