Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals. / McMahon, Michael; Lamont, Douglas J.; Beattie, Kenneth A.; Hayes, John D.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 44, 02.11.2010, p. 18838-18843.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals
A1 - McMahon,Michael
A1 - Lamont,Douglas J.
A1 - Beattie,Kenneth A.
A1 - Hayes,John D.
AU - McMahon,Michael
AU - Lamont,Douglas J.
AU - Beattie,Kenneth A.
AU - Hayes,John D.
PY - 2010/11/2
Y1 - 2010/11/2
N2 - 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.
AB - 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.
KW - TRANSCRIPTION FACTOR NRF2
KW - OXIDATIVE STRESS
KW - HEME OXYGENASE-1
KW - PROTEASOMAL DEGRADATION
KW - PHASE-2 ENZYMES
KW - CELLULAR STRESS
KW - INDUCTION
KW - PROTEIN
KW - ACTIVATION
KW - CELLS
U2 - 10.1073/pnas.1007387107
DO - 10.1073/pnas.1007387107
M1 - Article
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 44
VL - 107
SP - 18838
EP - 18843
ER -