NR1D/Rev-Erb Family 

Nuclear receptors, the largest superfamily of transcription factors, bind to specific DNA motifs in response to small molecule signaling.  The ligand binding domains (LBD) of nuclear receptors recognize and bind ligands (steroids, hormones, fatty acids, etc).  In doing so, the ligand binding domains function in regulating dimerization and association with coregulator proteins.  The Rev-Erbs are nuclear receptors that bind heme in there LBD.  Heme is a very unique ligand in proteins because the versatility of oxidation state and coordination environment enables the heme ligand to function as a multi-functional regulator involved in transcriptional regulation of circadian rhythm control. 


Circadian Rhythm Pathway

Ko CH, et al. (2006)  Hum Mol Genet. 15 Spec No 2:R271-7


 The circadian rhythm is a roughly 24-hour cycle responsible for orchestrating many biochemical, biophysical and behavioral processes through a complex transcriptional pathway regulated by the CLOCK protein.  CLOCK, a heme protein, is a crucial regulator of circadian rhythms. CLOCK regulates the activating portion of the circadian transcriptional feedback cycle by forming a heterodimeric complex with another transcription factor, BMAL1.  The CLOCK-BMAL1 heterodimers direct the transcription of: period (Per) and cryptochrome (Cry) proteins and retinoid related orphan nuclear receptors (ROR) and the Rev-Erb proteins. The Rev-Erbs act as transcriptional repressors; the transcription of the circadian clock protein BMAL1 is modulated through competition between Rev-erb reporessors and ROR activators.  Per and Cry are the negative regulatory components of the circadian clock.  Per and Cry inactivate the CLOCK-BMAL1 heterodimer thus completing the transcriptional loop.  Within the circadian transcriptional pathway, the transcription of the circadian clock protein, BMAL1, is modulated through competition between ROR activators and Rev-Erb repressors. Transcriptional regulation by these nuclear receptors plays an essential role in circadian rhythm, lipid and glucose metabolism.

We are interested in characterizing the heme environment of the Rev-Erbs using a variety of spectroscopic techniques.  Our goals are to identify ligands to the heme, determine if the protein is redox active, and probe the protein’s ability to bind small molecule gases including nitric oxide, carbon monoxide and hydrogen sulfide.