Details

Autor(en) / Beteiligte

• McMahon, Michael
• Lamont, Douglas J.
• Beattie, Kenneth A.
• Hayes, John D.
• Murphy, Mike P.

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2010-11, Vol.107 (44), p.18838-18843

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2010

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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, Zn²⁺, 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, Zn²⁺, and alkenals through three distinct sensors. The C288 alkenal sensor is of ancient origin, having evolved in a common ancestor of bilaterans. The Zn²⁺ 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, Zn²⁺, and alkenals, which collectively serve as second messengers that may signify danger and/or damage.