Nuclear receptors homo sapiens Rev-erbbeta and Drosophila melanogaster E75 are thiolate-ligated heme proteins which undergo redox-mediated ligand switching and bind CO and NO.
Nuclear receptors E75, which regulates development in Drosophila melanogaster, and Rev-erbbeta, which regulates circadian rhythm in humans, bind heme within their ligand binding domains (LBD). The heme-bound ligand binding domains of E75 and Rev-erbbeta were studied using electronic absorption, MCD, resonance Raman, and EPR spectroscopies. Both proteins undergo redox-dependent ligand switching and CO- and NO-induced ligand displacement. In the Fe(III) oxidation state, the nuclear receptor hemes are low spin and 6-coordinate with cysteine(thiolate) as one of the two axial heme ligands. The sixth ligand is a neutral donor, presumably histidine. When the heme is reduced to the Fe(II) oxidation state, the cysteine(thiolate) is replaced by a different neutral donor ligand, whose identity is not known. CO binds to the Fe(II) heme in both E75(LBD) and Rev-erbbeta(LBD) opposite a sixth neutral ligand, plausibly the same histidine that served as the sixth ligand in the Fe(III) state. NO binds to the heme of both proteins; however, the NO-heme is 5-coordinate in E75 and 6-coordinate in Rev-erbbeta. These nuclear receptors exhibit coordination characteristics that are similar to other known redox and gas sensors, suggesting that E75 and Rev-erbbeta may function in heme-, redox-, or gas-regulated control of cellular function.
Marvin
Katherine A
KA
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706, USA.
Reinking
Jeffrey L
JL
Lee
Andrea J
AJ
Pardee
Keith
K
Krause
Henry M
HM
Burstyn
Judith N
JN
D000818:Animals; D004331:Drosophila melanogaster / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D006420:Hemeproteins / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D010084:Oxidation-Reduction; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D013059:Spectrum Analysis, Raman; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D006420:Hemeproteins; D008024:Ligands; C090977:NR1D2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D013438:Sulfhydryl Compounds