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

• DOI: 10.1073/pnas.2016717118
• Publication Date: 2021-01-12T22:38:05Z
• Authors: Anindita Sarkar; Eric L. Carter; Jill B. Harland; Amy L. Speelman; Nicolai Lehnert; Stephen W. Ragsdale
• Keywords: Models, Molecular; Protein Conformation, alpha-Helical; 0301 basic medicine; Carbon Monoxide; 0303 health sciences; Binding Sites; Iron; Electron Spin Resonance Spectroscopy; Gene Expression; Biological Transport; Electrons; Heme; Nitric Oxide; Models, Biological; Circadian Rhythm; Electron Transport; 03 medical and health sciences; Escherichia coli; Humans; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Oxidation-Reduction; Protein Binding

Rev-Erbβ is a nuclear receptor that couples circadian rhythm, metabolism, and inflammation. Heme binding to the protein modulates its function as repressor, stability, ability bind other proteins, activity in gas sensing. binds Fe3+-heme more tightly than Fe2+-heme, suggesting activities may be regulated by heme redox state. Yet, this critical role of chemistry defining protein's resting state unknown. We demonstrate electrochemical whole-cell electron paramagnetic resonance experiments exists Fe3+ form within cell allowing replete even at low concentrations labile nucleus. However, being contradicts Rev-Erb's known sensor, which dogma asserts must Fe2+ This paper explains why congruent both with cellular show CO/NO elicits striking increase potential Fe3+/Fe2+ couple, characteristic an EC mechanism unfavorable Electrochemical reduction coupled highly favorable Chemical reaction binding, making spontaneous. Thus, Fe3+-Rev-Erbβ remains heme-loaded, crucial for repressor activity, undergoes when diatomic gases are present. work has broad implications proteins ligand-triggered changes cause conformational influencing or interprotein interactions (e.g., between NCoR1 Rev-Erbβ). study opens up possibility CO/NO-mediated regulation rhythm through Rev-Erbβ.