basic helix-loop-helix-orange (bHLH-O) domain found in transcription factor HES-5 and similar proteins; HES-5, also termed Class B basic helix-loop-helix protein 38 (bHLHb38), or hairy and enhancer of split 5, is a bHLH-O transcription factor that is involved in cell differentiation and proliferation in a variety of tissues. HES-5 is an essential effector for Notch signaling. It acts as a transducer of Notch signals in brain vascular development. It also acts as a key mediator of Wnt-3a-induced neuronal differentiation and plays a crucial role in normal inner ear hair cell development. HES-5 is one mammalian counterpart of the Hairy and Enhancer of split proteins that play a critical role in many physiological processes including cellular differentiation, cell cycle arrest, apoptosis and self-renewal ability.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1669945758   1 MRRDRINSSIEQLKLLLEQEFARHQPNSKLEKADILEMAVSYLKHSKAFA 50
Cdd:cd11461    10 TRRDRINSSIEQLKTLLEKEFQRHQPNSKLEKADILEMTVSFLKQSAKLS 59

basic helix-loop-helix-orange (bHLH-O) domain found in transcription factor HES-5 and similar proteins; HES-5, also termed Class B basic helix-loop-helix protein 38 (bHLHb38), or hairy and enhancer of split 5, is a bHLH-O transcription factor that is involved in cell differentiation and proliferation in a variety of tissues. HES-5 is an essential effector for Notch signaling. It acts as a transducer of Notch signals in brain vascular development. It also acts as a key mediator of Wnt-3a-induced neuronal differentiation and plays a crucial role in normal inner ear hair cell development. HES-5 is one mammalian counterpart of the Hairy and Enhancer of split proteins that play a critical role in many physiological processes including cellular differentiation, cell cycle arrest, apoptosis and self-renewal ability.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1669945758   1 MRRDRINSSIEQLKLLLEQEFARHQPNSKLEKADILEMAVSYLKHSKAFA 50
Cdd:cd11461    10 TRRDRINSSIEQLKTLLEKEFQRHQPNSKLEKADILEMTVSFLKQSAKLS 59

helix loop helix domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....
gi 1669945758    2 RRDRINSSIEQLKLLLEQefarHQPNSKLEKADILEMAVSYLKH 45
Cdd:smart00353   7 RRRKINEAFDELRSLLPT----LPKNKKLSKAEILRLAIEYIKS 46

Hairy Orange; The Orange domain is found in the Drosophila proteins Hesr-1, Hairy, and Enhancer of Split. The Orange domain is proposed to mediate specific protein-protein interaction between Hairy and Scute.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 1669945758  62 YSEGYSWCLQEAVQFLTLHAASDTQMK--LLYHFQR 95
Cdd:pfam07527   2 FRAGFNECANEVSRFLSTLEGVDPDLRqrLLNHLQR 37

basic helix-loop-helix-orange (bHLH-O) domain found in transcription factor HES-5 and similar proteins; HES-5, also termed Class B basic helix-loop-helix protein 38 (bHLHb38), or hairy and enhancer of split 5, is a bHLH-O transcription factor that is involved in cell differentiation and proliferation in a variety of tissues. HES-5 is an essential effector for Notch signaling. It acts as a transducer of Notch signals in brain vascular development. It also acts as a key mediator of Wnt-3a-induced neuronal differentiation and plays a crucial role in normal inner ear hair cell development. HES-5 is one mammalian counterpart of the Hairy and Enhancer of split proteins that play a critical role in many physiological processes including cellular differentiation, cell cycle arrest, apoptosis and self-renewal ability.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1669945758   1 MRRDRINSSIEQLKLLLEQEFARHQPNSKLEKADILEMAVSYLKHSKAFA 50
Cdd:cd11461    10 TRRDRINSSIEQLKTLLEKEFQRHQPNSKLEKADILEMTVSFLKQSAKLS 59

basic helix-loop-helix-orange (bHLH-O) domain found in hairy and enhancer of split (HES)-related repressor protein (HERP)-like family; The HERP-like family includes bHLH-O transcriptional regulators that are related to the Drosophila hairy and Enhancer-of-split proteins. They contain a basic helix-loop-helix (bHLH) domain with an invariant glycine residue in its basic region, an orange domain in the central region and YXXW sequence motif at its C-terminal region. HERP proteins (HEY1, HEY2 and HEYL) act as downstream effectors of Notch signaling. They are involved in cardiovascular development and have roles in somitogenesis, myogenesis and gliogenesis. Hairy and enhancer of split-related protein HELT is a transcriptional repressor expressed in the developing central nervous system. It binds preferentially to the canonical E box sequence 5'-CACGCG-3' and regulates neuronal differentiation and/or identity. Differentially expressed in chondrocytes proteins, DEC1 and DEC2, are widely expressed in both embryonic and adult tissues and have been implicated in apoptosis, cell proliferation, and circadian rhythms, as well as malignancy in various cancers. Drosophila melanogaster protein clockwork orange (Cwo) is also included in this family. It is involved in the regulation of Drosophila circadian rhythms. It functions as both an activator and a repressor of clock gene expression.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1669945758   2 RRDRINSSIEQLKLLLEQEFARHQpNSKLEKADILEMAVSYLKH 45
Cdd:cd11389     8 RRDRINESLAELRRLVPEARKSKG-SGKLEKAEILEMTLQHLKA 50

basic helix-loop-helix-orange (bHLH-O) domain found in transcription factor HES-3 and similar proteins; HES-3, also termed Class B basic helix-loop-helix protein 43 (bHLHb43), or hairy and enhancer of split 3, is a bHLH-O transcription factor expressed in neural stem and progenitor cells that is involved in tissue regeneration. It regulates gene expression, cell growth, and insulin release. HES-3 is one mammalian counterpart of the Hairy and Enhancer of split proteins that play a critical role in many physiological processes including cellular differentiation, cell cycle arrest, apoptosis and self-renewal ability.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1669945758   2 RRDRINSSIEQLKLLLEQEFARHQPNSKLEKADILEMAVSYLKH 45
Cdd:cd18933     5 RRARINVSLEQLKSLLEKHYSNNIRKRKLEKADILELTVKYLRS 48

basic helix-loop-helix-orange (bHLH-O) domain found in Drosophila melanogaster enhancer of split mbeta protein (ESMB) and similar proteins; ESMB, also termed E(spl)mbeta, or HLH-mbeta, or split locus enhancer protein mA, is a bHLH-O transcriptional repressor of genes that require a bHLH protein for their transcription. It is involved in the neural-epidermal lineage decision during early neurogenesis. The family also includes Enhancer of split m7 protein (also known as E(spl)m7), which acts as a transcriptional repressor that participates in the control of cell fate choice by uncommitted neuroectodermal cells in the embryo.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1669945758   2 RRDRINSSIEQLKLLLEQEFAR-HQPNSKLEKADILEMAVSYLK 44
Cdd:cd19741    19 RRARINKCLDELKDLMVEALATeAENVSKLEKADILELTVRHLK 62

helix loop helix domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....
gi 1669945758    2 RRDRINSSIEQLKLLLEQefarHQPNSKLEKADILEMAVSYLKH 45
Cdd:smart00353   7 RRRKINEAFDELRSLLPT----LPKNKKLSKAEILRLAIEYIKS 46

basic helix-loop-helix-orange (bHLH-O) domain found in hairy/enhancer-of-split related with YRPW motif-like protein (HEYL) and similar proteins; HEYL, also termed Class B basic helix-loop-helix protein 33 (bHLHb33), or hairy-related transcription factor 3 (HRT-3), is a bHLH-O transcriptional repressor that is strongly expressed in the presomitic mesoderm, the somites, the peripheral nervous system and smooth muscle of all arteries and is a downstream effector of the Notch and transforming growth factor-beta pathways. It promotes neuronal differentiation by activating proneural genes and inhibiting other hairy and enhancer of split (HES) and hairy/enhancer-of-split related with YRPW motif protein (HEY) proteins. HEYL also functions as a tumor suppressor involved in the progression of human cancers.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1669945758   2 RRDRINSSIEQLKLLLEQEFARhQPNSKLEKADILEMAVSYLK 44
Cdd:cd11447    20 RRDRINSSLSELRRLVPTAFEK-QGSSKLEKAEILQMTVDHLK 61

basic helix-loop-helix-orange (bHLH-O) domain found in hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1) and similar proteins; HEY1, also termed cardiovascular helix-loop-helix factor 2 (CHF-2), or Class B basic helix-loop-helix protein 31 (bHLHb31), or HES-related repressor protein 1, or hairy and enhancer of split-related protein 1 (HESR-1), or hairy-related transcription factor 1 (HRT-1), is a bHLH-O transcriptional repressor that acts as an essential downstream effector of the Notch signaling pathway and may play a fundamental role in vascular development. HEY1 also participates several cancer-related pathways. It acts as a positive regulator of the tumor suppressor p53.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1669945758   2 RRDRINSSIEQLKLLLEQEFARhQPNSKLEKADILEMAVSYLK--HSKAFAA 51
Cdd:cd19748    20 RRDRINNSLSELRRLVPSAFEK-QGSAKLEKAEILQMTVDHLKmlHAAGGKG 70

basic helix-loop-helix-orange (bHLH-O) domain found in hairy and enhancer of split-related protein HELT and similar proteins; HELT, also termed HES/HEY-like transcription factor, is a bHLH-O transcriptional repressor expressed in the developing central nervous system. It binds preferentially to the canonical E box sequence 5'-CACGCG-3' and regulates neuronal differentiation and/or identity. HELT could homodimerize and heterodimerize with other bHLH-O protein such as HES-5 or HEY-2 and bound to E box to repress gene transcription.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1669945758   2 RRDRINSSIEQLKLLLEQEFARhQPNSKLEKADILEMAVSYLK 44
Cdd:cd11408     9 RRDRINRCLNELGKTVPMALAK-QTSGKLEKAEILEMTVQYLR 50

basic helix-loop-helix-orange (bHLH-O) domain found in hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2) and similar proteins; HEY2, also termed cardiovascular helix-loop-helix factor 1 (CHF-1), or Class B basic helix-loop-helix protein 32 (bHLHb32), or HES-related repressor protein 2, or hairy and enhancer of split-related protein 2 (HESR-2), or hairy-related transcription factor 2 (HRT-2), or protein gridlock homolog, is a bHLH-O transcriptional repressor expressed preferentially in the developing and adult cardiovascular system. As a downstream effector of Notch signaling, HEY2 may be required for cardiovascular development. It also plays an important role in neurologic development, as well as in the progression of human cancers.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1669945758   2 RRDRINSSIEQLKLLLEQEFARhQPNSKLEKADILEMAVSYLKHSKA 48
Cdd:cd18920    21 RRDRINNSLSELRRLVPTAFEK-QGSAKLEKAEILQMTVDHLKMLQA 66

basic Helix Loop Helix (bHLH) domain superfamily; bHLH proteins are transcriptional regulators that are found in organisms from yeast to humans. Members of the bHLH superfamily have two highly conserved and functionally distinct regions. The basic part is at the amino end of the bHLH that may bind DNA to a consensus hexanucleotide sequence known as the E box (CANNTG). Different families of bHLH proteins recognize different E-box consensus sequences. At the carboxyl-terminal end of the region is the HLH region that interacts with other proteins to form homo- and heterodimers. bHLH proteins function as a diverse set of regulatory factors because they recognize different DNA sequences and dimerize with different proteins. The bHLH proteins can be divided to cell-type specific and widely expressed proteins. The cell-type specific members of bHLH superfamily are involved in cell-fate determination and act in neurogenesis, cardiogenesis, myogenesis, and hematopoiesis.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1669945758   2 RRDRINSSIEQLKLLLEQefarHQPNSKLEKADILEMAVSYLKHSKA 48
Cdd:cd00083     4 RRDKINDAFEELKRLLPE----LPDSKKLSKASILQKAVEYIRELQS 46

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain family; bHLH-PAS domain has been found in a large group of bHLH transcription regulators that are involved in gene expression responding to environmental change and controlling aspects of neural development, including proteins from aryl hydrocarbon receptor nuclear translocator (ARNT) family, hypoxia-inducible factor (HIF) family, aryl hydrocarbon receptor (AhR) family, neuronal PAS domain-containing protein (NPAS) family, Circadian locomotor output cycles protein kaput (CLOCK)-like family, and single-minded (SIM) family. bHLH-PAS transcriptional regulatory factors have a bHLH DNA-binding domain followed by two PAS domains and a C-terminal activation or repression domain. bHLH-PAS family members can be divided into class I and class II based on their dimerization partner. bHLH-PAS class I factors include AhR, HIF and SIM. The best characterized bHLH-PAS Class II protein is the ubiquitous ARNT. Some members of bHLH-PAS family act as transcriptional coactivators (such as NCoA) that lack the ability to dimerize and bind DNA.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1669945758   2 RRDRINSSIEQLKLLLEQEFArhqPNSKLEKADILEMAVSYLK 44
Cdd:cd11391    11 RRDKENAEISELASLLPLPPA---VGSKLDKLSVLRLAVAYLR 50

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in USF/MITF family; The USF (upstream stimulatory factor)/MITF (microphthalmia-associated transcription factor) family includes two bHLHzip transcription factor subfamilies. USFs are ubiquitously expressed and key regulators of a wide number of gene regulation networks, including the stress and immune responses, cell cycle and proliferation, lipid and glucid metabolism. USFs recruit chromatin remodeling enzymes and interact with co-activators and the members of the transcription pre-initiation complex. USFs interact with high affinity to E-box regulatory elements. The MITF (also known as microphthalmia-TFE, or MiT) subfamily comprises four genes in mammals (MITF, TFE3, TFEB, and TFEC); each gene has different functions. MITF is involved in neural crest melanocytes development as well as the pigmented retinal epithelium. TFEB is required for vascularization of the mouse placenta. TFE3 is involved in B cell function. TFEC regulates gene expression in macrophages. The MITF subfamily proteins can form homodimers or heterodimers with each other but not with other bHLH or bHLHzip proteins.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1669945758   2 RRDRINSSIEQLKLLLEQEFaRHQPNSKLEKADILEMAVSYLKH 45
Cdd:cd11387     9 RRDNINEKIQELGSLVPPSR-LETKDLKPNKGSILSKAVEYIRE 51

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in aryl hydrocarbon receptor (AhR) and similar proteins; AhR, also termed Ah receptor, or Dioxin receptor (DR), or Class E basic helix-loop-helix protein 76 (bHLHe76), is the only member of bHLH-PAS transcription regulators that bind and be activated by small chemical ligands. It is activated by Dioxin to control the expression of certain genes to influence biological processes such as apoptosis, proliferation, cell growth and differentiation. To form active DNA binding complexes AhR dimerize with a bHLH-PAS factor ARNT (Aryl hydrocarbon Nuclear Receptor Translocator).

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1669945758   3 RDRINSSIEQLKLLL--EQEFArhqpnSKLEKADILEMAVSYLKHSKAFAAA 52
Cdd:cd11436    13 RDRLNTELDRLASLLpfPQDVI-----SKLDKLSVLRLSVSYLRAKSFFDVA 59

Hairy Orange; The Orange domain is found in the Drosophila proteins Hesr-1, Hairy, and Enhancer of Split. The Orange domain is proposed to mediate specific protein-protein interaction between Hairy and Scute.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 1669945758  62 YSEGYSWCLQEAVQFLTLHAASDTQMK--LLYHFQR 95
Cdd:pfam07527   2 FRAGFNECANEVSRFLSTLEGVDPDLRqrLLNHLQR 37

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in the aryl hydrocarbon receptor (AhR) family; The AhR family includes AhR, AhR repressor (AhRR) and Drosophila melanogaster protein spineless. AhR, also termed Ah receptor, or Dioxin receptor (DR), or Class E basic helix-loop-helix protein 76 (bHLHe76), is the only member of bHLH-PAS transcription regulators that bind and be activated by small chemical ligands. It is activated by Dioxin to control the expression of certain genes to influence biological processes such as apoptosis, proliferation, cell growth and differentiation. To form active DNA binding complexes AhR dimerizes with a bHLH-PAS factor ARNT (Aryl hydrocarbon Nuclear Receptor Translocator). AhRR, also termed Class E basic helix-loop-helix protein 77 (bHLHe77), is a member of bHLH-PAS transcription factors that acts as a negative regulator of AhR, playing key roles in development and environmental sensing. AhRR functions by competing with AhR for its partner ARNT. AhRR-ARNT complexes are transcriptionally inactive. Spineless is a bHLH-PAS transcription factor that plays an important role in fly morphogenesis. It is both necessary and sufficient for the formation of the ommatidial mosaic.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1669945758   3 RDRINSSIEQL-KLLLEQEFARhqpnSKLEKADILEMAVSYLKHSKAFAAA 52
Cdd:cd19696    12 RDRLNSELDELaSLLPFPEDVI----SKLDKLSVLRLSVSYLRTKNYFQAV 58

basic helix-loop-helix (bHLH) domain found in the spermatogenesis- and oogenesis-specific basic helix-loop-helix-containing protein (SOHLH) family and similar proteins; The SOHLH family includes two bHLH transcription factors, SOHLH1 and SOHLH2. They are specifically in spermatogonia and oocytes and essential for early spermatogonial and oocyte differentiation. The family also includes transcription factor-like 5 protein (TCFL5) and similar proteins. TCFL5, also termed Cha transcription factor, or HPV-16 E2-binding protein 1 (E2BP-1), is a bHLH transcription factor that plays a crucial role in spermatogenesis. It regulates cell proliferation or differentiation of cells through binding to a specific DNA sequence like other bHLH molecules.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1669945758   1 MRRDRINSSIEQLKLLLeqefarhqP--NSKLEKADILEMAVSYLKH 45
Cdd:cd19683    12 QRRERIKIACDQLRKLV--------PgcSRKTDKATVFEFTVAYIKF 50

basic helix-loop-helix-orange (bHLH-O) domain found in Drosophila melanogaster Enhancer of split proteins, E(spl)m5, E(spl)m8 and similar proteins; The family includes two bHLH-O transcriptional repressors, E(spl)m5 and E(spl)m8, which participate in the control of cell fate choice by uncommitted neuroectodermal cells in the embryo. They bind DNA on N-box motifs, 5'-CACNAG-3'.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1669945758   2 RRDRINSSIEQLKLLLEQefARHQPNS-KLEKADILEMAVSYLKHSK 47
Cdd:cd18916    11 RRARINKCLSELKTLVAE--CSGDDGClRMDKAEMLETAVAFMRQQQ 55

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in MLX-interacting protein (MLXIP), MLX-interacting protein-like (MLXIPL) and similar proteins; The family includes MLXIP and MLXIPL. MLXIP, also termed Class E basic helix-loop-helix protein 36 (bHLHe36), or transcriptional activator MondoA, is a bHLHZip transcriptional activator that binds DNA as a heterodimer with Mlx. It binds to the canonical E box sequence 5'-CACGTG-3' and plays a role in transcriptional activation of glycolytic target genes. MLXIP is most highly expressed in skeletal muscle and functions as an indirect glucose sensor, by sensing glucose 6-phosphate and shuttling between the nucleus and the cytoplasm. MLXIPL, also termed carbohydrate-responsive element-binding protein (ChREBP), or Class D basic helix-loop-helix protein 14 (bHLHd14), or MLX interactor, or WS basic-helix-loop-helix leucine zipper protein (WS-bHLH), or Williams-Beuren syndrome chromosomal region 14 protein (WBSCR14), is a bHLHZip transcriptional factor integral to the regulation of glycolysis and lipogenesis in the liver. It forms heterodimers with the bHLHZip protein Mlx to bind the DNA sequence 5'-CACGTG-3'.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1669945758   2 RRDRINSSIEQLKLLLEQefARHQPNSKLEKADILEMAVSYLKHSKA 48
Cdd:cd11405    14 RRFNIKSGFDTLQSLIPS--LGQNPNQKVSKAAMLQKAAEYIKSLKR 58