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        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 18858789  13 KRILKPVIEKKRRDRINQRLEELRTLLLDNTLDSRLQNPKLEKAEILELAVEYIRTKTATA 73
Cdd:cd11462   1 RKLLKPLVEKRRRDRINRSLEELRVLLLQNTQDEKLKNPKVEKAEILELTVQFLRNSSLSA 61

basic helix-loop-helix-orange (bHLH-O) domain found in hairy and enhancer of split 7 (HES-7) and similar proteins; HES-7, also termed Class B basic helix-loop-helix protein 37 (bHLHb37), or bHLH factor Hes7, is a bHLH-O transcriptional repressor that is expressed in an oscillatory manner and acts as a key regulator of the pace of the segmentation clock. It is regulated by the Notch and Fgf/Mapk pathways. HES-7 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        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 18858789  13 KRILKPVIEKKRRDRINQRLEELRTLLLDNTLDSRLQNPKLEKAEILELAVEYIRTKTATA 73
Cdd:cd11462   1 RKLLKPLVEKRRRDRINRSLEELRVLLLQNTQDEKLKNPKVEKAEILELTVQFLRNSSLSA 61

helix loop helix domain;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 18858789     18 PVIEKKRRDRINQRLeelrtllldNTLDSRL----QNPKLEKAEILELAVEYIR 67
Cdd:smart00353   1 NARERRRRRKINEAF---------DELRSLLptlpKNKKLSKAEILRLAIEYIK 45

basic helix-loop-helix-orange (bHLH-O) domain found in hairy and enhancer of split 7 (HES-7) and similar proteins; HES-7, also termed Class B basic helix-loop-helix protein 37 (bHLHb37), or bHLH factor Hes7, is a bHLH-O transcriptional repressor that is expressed in an oscillatory manner and acts as a key regulator of the pace of the segmentation clock. It is regulated by the Notch and Fgf/Mapk pathways. HES-7 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        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 18858789  13 KRILKPVIEKKRRDRINQRLEELRTLLLDNTLDSRLQNPKLEKAEILELAVEYIRTKTATA 73
Cdd:cd11462   1 RKLLKPLVEKRRRDRINRSLEELRVLLLQNTQDEKLKNPKVEKAEILELTVQFLRNSSLSA 61

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 18858789  14 RILKPVIEKKRRDRINQRLEELRTLLLDNTLDSRlQNPKLEKAEILELAVEYIRTKTA 71
Cdd:cd11461   1 KLRKPVVEKTRRDRINSSIEQLKTLLEKEFQRHQ-PNSKLEKADILEMTVSFLKQSAK 57

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        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 18858789  19 VIEKKRRDRINQRLeelrtllldNTLDS-------RLQNPKLEKAEILELAVEYIRTKTAT 72
Cdd:cd11389   3 VIEKRRRDRINESL---------AELRRlvpearkSKGSGKLEKAEILEMTLQHLKALQSS 54

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        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 18858789  19 VIEKKRRDRINQRLEELRTLLLDNTldSRLQNPKLEKAEILELAVEYIRTKTAT 72
Cdd:cd11408   4 VIEKRRRDRINRCLNELGKTVPMAL--AKQTSGKLEKAEILEMTVQYLRALHSA 55

basic helix-loop-helix-orange (bHLH-O) domain found in hairy and enhancer of split (HES)-related repressor protein (HERP) family; HERP (also called Hey/Hesr/HRT/CHF/gridlock) proteins corresponds to a family of bHLH-O transcriptional repressors that are related to the Drosophila hairy and Enhancer-of-split proteins and act as downstream effectors of Notch signaling. 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 are involved in cardiovascular development and have roles in somitogenesis, myogenesis and gliogenesis.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 18858789  19 VIEKKRRDRINqrleelrtllldNTL-DSRLQNP---------KLEKAEILELAVEYIRTKTAT 72
Cdd:cd11407   7 IIEKRRRDRIN------------NSLaELRRLVPtafekqgsaKLEKAEILQMTVDHLKMLHSK 58

helix loop helix domain;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 18858789     18 PVIEKKRRDRINQRLeelrtllldNTLDSRL----QNPKLEKAEILELAVEYIR 67
Cdd:smart00353   1 NARERRRRRKINEAF---------DELRSLLptlpKNKKLSKAEILRLAIEYIK 45

basic helix-loop-helix-orange (bHLH-O) domain found in transcription factor HES-6 and similar proteins; HES-6, also termed Class B basic helix-loop-helix protein 41 (bHLHb41), or hairy and enhancer of split 6, or C-HAIRY1, is a bHLH-O transcription factor that is expressed in developing muscle and involved in angiogenesis, myogenesis, neural differentiation and neurogenesis. HES-6 antagonizes Notch signaling but is not regulated by Notch signaling. It is a transcription co-factor associated with stem cell characteristics in neural tissue. It may act as an inhibitor of Hes-1 during neuronal development and forms a heterodimer with HES-1 to prevent its association with transcriptional co-repressors. The overexpression of HES-6 has been reported in metastatic cancers of different origins. HES-6 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 18858789  13 KRILKPVIEKKRRDRINQRLEELRTLLLDNTLDSrlqnpKLEKAEILELAVEYIR 67
Cdd:cd11460   3 RKARKPLVEKKRRARINESLQELRLILADAELQS-----KMENAEVLELTVKRVQ 52

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        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 18858789   2 VTPKMASRRptKRilKPVIEKKRRDRINQRLEELRTLLLdnTLDSRLQNPKLEKAEILELAVEYIRTKTATA 73
Cdd:cd11447   2 TSSQIQARK--KR--RGIIEKRRRDRINSSLSELRRLVP--TAFEKQGSSKLEKAEILQMTVDHLKMLHATG 67

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 18858789  20 IEKKRRDRINQRLEELRTLLLDNtLDSRLQNPKLEKAEILELAVEYIRT 68
Cdd:cd18933   1 MEKKRRARINVSLEQLKSLLEKH-YSNNIRKRKLEKADILELTVKYLRS 48

basic helix-loop-helix-orange (bHLH-O) domain found in hairy and enhancer of split 2 (HES-2) and similar proteins; HES-2, also termed Class B basic helix-loop-helix protein 40 (bHLHb40), is a bHLH-O transcriptional repressor of genes that require a bHLH protein for their transcription. It acts as a negative regulator through interaction with both E-box and N-box sequences. HES-2 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 18858789  13 KRILKPVIEKKRRDRINQRLEELRTLLLDNTLDSRLQNPKLEKAEILELAVEYIR 67
Cdd:cd11463   5 RKTLKPLMEKRRRARINESLNQLKTLILPLVGKDSSRYSKLEKADILEMTVRFLQ 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        40
                  ....*....|....*....|....*....|....*....|
gi 18858789   118 YKAGFKECISRSASFIDCVEPSQRDsFVQGLCHHLDSYSS 157
Cdd:pfam07527   2 FRAGFNECANEVSRFLSTLEGVDPD-LRQRLLNHLQRCLA 40

basic helix-loop-helix-orange (bHLH-O) domain found in differentially expressed in chondrocytes protein (DEC) family; The DEC family includes two bHLH-O transcriptional repressors, DEC1 and DEC2, which 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. They mediate the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes. They are induced by CLOCK:BMAL1 heterodimer via the CACGTG E-box in the promoter.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 18858789  10 RPTKRILKPVIEKKRRDRINQRLEELRTLLLDNTLDSRLQNpkLEKAEILELAVEYIRTKTATARDQ 76
Cdd:cd11409   1 KETYKLPHRLIEKKRRDRINECIAQLKDLLPEHLKLTTLGH--LEKAVVLELTLKHLKALTALTEQQ 65