The Orange domain is a motif of ~35 amino acids present in eukaryotic DNA-binding transcription repressors, which regulate cell differentiation, embryonic patterning and other biological processes in both vertebrates and invertebrates. The Orange domain is located just C-terminal to a basic helix-loop-helix (bHLH) domain in the bHLH-Orange (bHLH-O) proteins. This family of bHLH repressors is related to the Drosophila hairy and Enhancer-of-split proteins, wherein the Orange domain was first described and also named helix III/IV region [ (PUBMED:8524259) (PUBMED:1427040) ]. The transcription of many vertebrate bHLH-O genes is regulated by the Notch signaling pathway, which controls fate decisions and other developmental processes. Orange domain proteins function as transcription repressors involved in the regulation of differentiation, anteroposterior segmentation and sex determination in flies [ (PUBMED:11840327) ].
Four subfamilies of bHLH-Orange proteins have been identified, i.e. hairy, Enhancer of split, Hey (also named HRT or Hesr) and Stra13 (also named SHARP, DEC, CLAST or BHLHB2) [ (PUBMED:11840327) (PUBMED:11162494) ]. All these Orange domain proteins have the bHLH domain and except for the Stra13 subfamily, the other subfamily members have a conserved tetrapeptide motif in the C-terminal extremity. The C-terminal motif of the hairy and Enhancer of split proteins is WRPW and this binds the transcriptional corepressor groucho/TLE. For the Hey subfamily members the C-terminal motif is YXXW. The Orange domain may confer specificity of function to different family members and/or it may be involved in dimerization [ (PUBMED:8524259) (PUBMED:11840327) ].
GO process:
regulation of transcription, DNA-templated (GO:0006355)
Identification and expression of a novel family of bHLH cDNAs related to Drosophila hairy and enhancer of split.
Biochem Biophys Res Commun. 1999; 260: 459-65
Display abstract
In this report we describe the initial characterization of murine, human, and Drosophila hesr-1 (for hairy and enhancer of split related-1) a novel evolutionary conserved family of hairy/enhancer of split homologs. Hesr-1 cDNAs display features typical of hairy and enhancer of split-type bHLH proteins including a N-terminal bHLH domain a conserved orange domain immediately C-terminal to the bHLH region. Despite their similarity to known hairy/enhancer of split homologs, hesr-1 cDNAs are divergent members of the hairy and enhancer of split bHLH family since the degree of sequence identity within the bHLH and their nearest homologs are relatively low. Moreover, the tetrapeptide motif, WRPW, which is found in all hairy and enhancer of split family members, is not present in hesr-1. Rather, a variant of this motif, YRPW, is found. Analysis of embryonic murine hesr-1 expression by in situ hybridization reveals strong expression in the somitic mesoderm, the central nervous system, the kidney, the heart, nasal epithelium, and limbs indicating a role for hesr-1 in the development of these tissues. Like the enhancer of split cDNAs in Drosophila, we show that hesr-1 expression depends critically on signaling through the notch pathway in murine embryos, suggesting that aspects of hesr-1 regulation and function might also be evolutionary conserved.
Specificity for the hairy/enhancer of split basic helix-loop-helix (bHLH) proteins maps outside the bHLH domain and suggests two separable modes of transcriptional repression.
Mol Cell Biol. 1995; 15: 6923-31
Display abstract
The Hairy/Enhancer of split/Deadpan family of basic helix-loop-helix (bHLH) proteins function as transcriptional repressors. We have examined the mechanisms of repression used by the Hairy and E(SPL) proteins by assaying the antagonism between wild-type or altered Hairy/E(SPL) and Scute bHLH proteins during sex determination in Drosophila melanogaster. Domain swapping and mutagenesis of the Hairy and E(SPL) proteins show that three evolutionarily conserved domains are required for their function: the bHLH, Orange, and WRPW domains. However, the suppression of Scute activity by Hairy does not require the WRPW domain. We show that the Orange domain is an important functional domain that confers specificity among members of the Hairy/E(SPL) family. In addition, we show that a Xenopus Hairy homology conserves not only Hairy's structure but also its biological activity in our assays. We propose that transcriptional repression by the Hairy/E(SPL) family of bHLH proteins involves two separable mechanisms: repression of specific transcriptional activators, such as Scute, through the bHLH and Orange domains and repression of other activators via interaction of the C-terminal WRPW motif with corepressors, such as the Groucho protein.
Metabolism (metabolic pathways involving proteins which contain this domain)
This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with ORANGE domain which could be assigned to a KEGG orthologous group, and not all proteins containing ORANGE domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.
