PROSITE documentation PDOC00038

Myc-type, basic helix-loop-helix (bHLH) domain profile

A number of eukaryotic proteins, which probably are sequence specific DNA-binding proteins that act as transcription factors, share a conserved domain of 40 to 50 amino acid residues. It has been proposed [1] that this domain is formed of two amphipathic helices joined by a variable length linker region that could form a loop. This 'helix-loop-helix' (HLH) domain mediates protein dimerization and has been found in the proteins listed below [2,3]. Most of these proteins have an extra basic region of about 15 amino acid residues that is adjacent to the HLH domain and specifically binds to DNA. They are refered as basic helix-loop-helix proteins (bHLH), and are classified in two groups: class A (ubiquitous) and class B (tissue-specific). Members of the bHLH family bind variations on the core sequence 'CANNTG', also refered to as the E-box motif. The homo- or heterodimerization mediated by the HLH domain is independent of, but necessary for DNA binding, as two basic regions are required for DNA binding activity. The HLH proteins lacking the basic domain (Emc, Id) function as negative regulators since they form heterodimers, but fail to bind DNA. The hairy-related proteins (hairy, E(spl), deadpan) also repress transcription although they can bind DNA. The proteins of this subfamily act together with co-repressor proteins, like groucho, through their C-terminal motif WRPW.

• The myc family of cellular oncogenes [4], which is currently known to contain four members: c-myc, N-myc, L-myc, and B-myc. The myc genes are thought to play a role in cellular differentiation and proliferation.
• Proteins involved in myogenesis (the induction of muscle cells). In mammals MyoD1 (Myf-3), myogenin (Myf-4), Myf-5, and Myf-6 (Mrf4 or herculin), in birds CMD1 (QMF-1), in Xenopus MyoD and MF25, in Caenorhabditis elegans CeMyoD, and in Drosophila nautilus (nau).
• Vertebrate proteins that bind specific DNA sequences ('E boxes') in various immunoglobulin chains enhancers: E2A or ITF-1 (E12/pan-2 and E47/pan-1), ITF-2 (tcf4), TFE3, and TFEB.
• Vertebrate neurogenic differentiation factor 1 that acts as differentiation factor during neurogenesis.
• Vertebrate MAX protein, a transcription regulator that forms a sequence- specific DNA-binding protein complex with myc or mad.
• Vertebrate Max Interacting Protein 1 (MXI1 protein) which acts as a transcriptional repressor and may antagonize myc transcriptional activity by competing for max.
• Proteins of the bHLH/PAS superfamily which are transcriptional activators. In mammals, AH receptor nuclear translocator (ARNT), single-minded homologs (SIM1 and SIM2), hypoxia-inducible factor 1 α (HIF1A), AH receptor (AHR), neuronal pas domain proteins (NPAS1 and NPAS2), endothelial pas domain protein 1 (EPAS1), mouse ARNT2, and human BMAL1. In drosophila, single-minded (SIM), AH receptor nuclear translocator (ARNT), trachealess protein (TRH), and similar protein (SIMA).
• Mammalian transcription factors HES, which repress transcription by acting on two types of DNA sequences, the E box and the N box.
• Mammalian MAD protein (max dimerizer) which acts as transcriptional repressor and may antagonize myc transcriptional activity by competing for max.
• Mammalian Upstream Stimulatory Factor 1 and 2 (USF1 and USF2), which bind to a symmetrical DNA sequence that is found in a variety of viral and cellular promoters.
• Human lyl-1 protein; which is involved, by chromosomal translocation, in T- cell leukemia.
• Human transcription factor AP-4.
• Mouse helix-loop-helix proteins MATH-1 and MATH-2 which activate E box- dependent transcription in collaboration with E47.
• Mammalian stem cell protein (SCL) (also known as tal1), a protein which may play an important role in hemopoietic differentiation. SCL is involved, by chromosomal translocation, in stem-cell leukemia.
• Mammalian proteins Id1 to Id4 [5]. Id (inhibitor of DNA binding) proteins lack a basic DNA-binding domain but are able to form heterodimers with other HLH proteins, thereby inhibiting binding to DNA.
• Drosophila extra-macrochaetae (emc) protein, which participates in sensory organ patterning by antagonizing the neurogenic activity of the achaete- scute complex. Emc is the homolog of mammalian Id proteins.
• Human Sterol Regulatory Element Binding Protein 1 (SREBP-1), a transcriptional activator that binds to the sterol regulatory element 1 (SRE-1) found in the flanking region of the LDLR gene and in other genes.
• Drosophila achaete-scute (AS-C) complex proteins T3 (l'sc), T4 (scute), T5 (achaete) and T8 (asense). The AS-C proteins are involved in the determination of the neuronal precursors in the peripheral nervous system and the central nervous system.
• Mammalian homologs of achaete-scute proteins, the MASH-1 and MASH-2 proteins.
• Drosophila atonal protein (ato) which is involved in neurogenesis.
• Drosophila daughterless (da) protein, which is essential for neurogenesis and sex-determination.
• Drosophila deadpan (dpn), a hairy-like protein involved in the functional differentiation of neurons.
• Drosophila delilah (dei) protein, which is plays an important role in the differentiation of epidermal cells into muscle.
• Drosophila hairy (h) protein, a transcriptional repressor which regulates the embryonic segmentation and adult bristle patterning.
• Drosophila enhancer of split proteins E(spl), that are hairy-like proteins active during neurogenesis. also act as transcriptional repressors.
• Drosophila twist (twi) protein, which is involved in the establishment of germ layers in embryos.
• Maize anthocyanin regulatory proteins R-S and LC.
• Yeast centromere-binding protein 1 (CPF1 or CBF1). This protein is involved in chromosomal segregation. It binds to a highly conserved DNA sequence, found in centromers and in several promoters.
• Yeast INO2 and INO4 proteins.
• Yeast phosphate system positive regulatory protein PHO4 which interacts with the upstream activating sequence of several acid phosphatase genes.
• Yeast serine-rich protein TYE7 that is required for ty-mediated ADH2 expression.
• Neurospora crassa nuc-1, a protein that activates the transcription of structural genes for phosphorus acquisition.
• Fission yeast protein esc1 which is involved in the sexual differentiation process.

The schematic representation of the helix-loop-helix domain is shown here:

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        Amphipathic helix 1         Loop          Amphipathic helix 2

The profile we developed covers the helix-loop-helix dimerization domain and the basic region.