![]() ![]() Unfortunately, there is no 3D structure described for a mammalian BHLHE41 in Genbank’s Protein Data Bank to determine the spatial effects of amino acid variants.īecause of its essential function in sleep regulation, anomalies in clock genes can lead to abnormal patterns of sleep that can manifest in a wide variety of ways, ranging from insomnia to oversleeping. These domains are conserved between humans and zebrafish in both their amino acid composition and function. The other well studied conserved domain in BHLHE41 is the orange domain which provides specificity as a transcriptional repressor. As a member of the group E bHLH family, this protein specifically binds to an N-box sequence (CACGCG or CACGAG) based on BHLHE41 amino acid site 53 (glutamate). The DNA-binding region is followed by two alpha-helices surrounding a variable loop region. Specifically, the bHLH domain is composed of a DNA-binding region, E-box/N-box specificity site, and a dimerization interface for polypeptide binding. As a member of the bHLH family, BHLHE41 contains a ~60 amino acid bHLH conserved domain that promotes dimerization and DNA binding. īHLHE41 has several conserved functional domains including a bHLH region and the “orange” domain. Furthermore, disabling orexin results in narcolepsy in mammals, confirming that orexin plays a vital role in sleep regulation. Specifically, by binding to the promoter region on the prepro-orexin gene, BHLHE41 acts as a repressor of orexin expression in mammals. It is an essential clock protein that acts as a transcription factor which maintains the negative feedback loop in the circadian clock by repressing E-box-mediated transcription. Īmong the genes responsible for circadian regulation in mammals is the basic helix-loop-helix family member e41, also known as “differentially expressed in chondrocytes protein 2” ( DEC2). The timing and duration of sleep varies widely among mammals and is regulated by a plethora of intricate mechanisms including many circadian clock genes. ![]() It is essential in maintaining both physical and mental health, especially in humans where sleep deprivation is linked to diabetes, high blood pressure, obesity, and decreased immune function. ![]() Sleep plays a vital function for survival in animals, especially vertebrates and even some invertebrates. Given the strong signal of purifying selection across this gene, phylogenetic congruence with expected relationships and generally conserved function among mammals investigated thus far, we suggest the indels predicted in the gorilla BHLHE41 may represent an annotation error and warrant experimental validation. Unexpectedly, the gorilla BHLHE41 sequence has a 318 bp insertion at the 5’ end of the coding sequence and a deletion of 195 bp near the 3’ end of the coding sequence (including the two short sleeper variable sites). Significant purifying selection was detected in about two-thirds of the variable codons and no codons exhibited significant signs of positive selection. Phylogenetic analyses based on the nucleotides of the coding sequence alignment are consistent with established mammalian relationships confirming orthology among the sampled sequences. No other mammals had the same “short-sleeper” amino acid substitutions previously described from humans. Approximately half of the coding sequence was invariable at the nucleotide level and close to three-quarters of the amino acid alignment was identical. ![]() We compare BHLHE41 coding sequences for 27 mammals. In humans, “short-sleeper” behavior has been linked to specific amino acid substitutions in BHLHE41 (DEC2), yet little is known about variation at these sites and across this gene in mammals. There is a molecular basis for many sleep patterns and disorders involving circadian clock genes. ![]()
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