Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals

Michael McMahon (Lead / Corresponding author), Douglas J. Lamont, Kenneth A. Beattie, John D. Hayes

    Research output: Contribution to journalArticlepeer-review

    266 Citations (Scopus)

    Abstract

    Recognition and repair of cellular damage is crucial if organisms are to survive harmful environmental conditions. In mammals, the Keap1 protein orchestrates this response, but how it perceives adverse circumstances is not fully understood. Herein, we implicate NO, Zn(2+), and alkenals, endogenously occurring chemicals whose concentrations increase during stress, in this process. By combining molecular modeling with phylogenetic, chemical, and functional analyses, we show that Keap1 directly recognizes NO, Zn(2+), and alkenals through three distinct sensors. The C288 alkenal sensor is of ancient origin, having evolved in a common ancestor of bilaterans. The Zn(2+) sensor minimally comprises H225, C226, and C613. The most recent sensor, the NO sensor, emerged coincident with an expansion of the NOS gene family in vertebrates. It comprises a cluster of basic amino acids (H129, K131, R135, K150, and H154) that facilitate S-nitrosation of C151. Taken together, our data suggest that Keap1 is a specialized sensor that quantifies stress by monitoring the intracellular concentrations of NO, Zn(2+), and alkenals, which collectively serve as second messengers that may signify danger and/or damage.
    Original languageEnglish
    Pages (from-to)18838-18843
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume107
    Issue number44
    DOIs
    Publication statusPublished - 2 Nov 2010

    Keywords

    • TRANSCRIPTION FACTOR NRF2
    • OXIDATIVE STRESS
    • HEME OXYGENASE-1
    • PROTEASOMAL DEGRADATION
    • PHASE-2 ENZYMES
    • CELLULAR STRESS
    • INDUCTION
    • PROTEIN
    • ACTIVATION
    • CELLS

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