January 15, 2021

The Ragsdale lab publishes a research article in PNAS

Ferric heme as a CO/NO sensor in the nuclear receptor Rev-Erbβ by coupling gas binding to electron transfer

Rev-Erbβ is a heme-responsive transcription factor, yet the role of heme redox chemistry in regulating the protein’s heme occupancy and function as a repressor and gas sensor has been elusive. In work newly published in PNAS, researchers in the laboratory of Stephen Ragsdale and their collaborators in the Chemistry and Biophysics Departments used electrochemical and whole-cell electron paramagnetic resonance experiments to show that Rev-Erbβ exists in the Fe3+-heme bound state within the cell. Although being in the Fe3+ redox state seems incompatible with Rev-Erbβ's function as a gas sensor, the authors show that the binding of CO/NO elicits a striking increase in the redox potential of the Fe3+/Fe2+ couple, consistent with an EC mechanism in which the unfavorable Electrochemical reduction of heme is coupled to the highly favorable Chemical reaction of gas binding. This study opens up the possibility of CO/NO-mediated regulation of circadian rhythm through redox changes in Rev-Erbβ and has broad implications for proteins involved in many other biological processes, including drug metabolism and the global carbon cycle.

The redox fate of a heme protein in the presence of signaling gases. The Fe3+-heme bound form of Rev-Erbβ predominates in cells, and binding of the signaling gases CO and NO is coupled to electrochemical reduction of heme. This thermodynamic coupling allows Rev-Erbβ to remain heme-loaded, which is crucial for its activity as a transcriptional repressor, and to undergo reduction when signaling gases are present.