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 238637265  19 KLRKPMVEKIRRERINSSIEKLKTLLAQEFVKQQPDSRQEKADILEMTLDFLRRSQKSS 77
Cdd:cd11461    1 KLRKPVVEKTRRDRINSSIEQLKTLLEKEFQRHQPNSKLEKADILEMTVSFLKQSAKLS 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 238637265  19 KLRKPMVEKIRRERINSSIEKLKTLLAQEFVKQQPDSRQEKADILEMTLDFLRRSQKSS 77
Cdd:cd11461    1 KLRKPVVEKTRRDRINSSIEQLKTLLEKEFQRHQPNSKLEKADILEMTVSFLKQSAKLS 59

Orange domain; This domain confers specificity among members of the Hairy/E(SPL) family.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 238637265    77 SAAGDGRSRCVQEAVSFLSQCPVQTQshTRLMKLFLHMQTPADQHTR 123
Cdd:smart00511   1 SSFRSGYRECANEVSRFLSQLPGTDP--DVRARLLSHLQTHLNQLLQ 45

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 238637265  19 KLRKPMVEKIRRERINSSIEKLKTLLAQEFVKQQPDSRQEKADILEMTLDFLRRSQKSS 77
Cdd:cd11461    1 KLRKPVVEKTRRDRINSSIEQLKTLLEKEFQRHQPNSKLEKADILEMTVSFLKQSAKLS 59

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 238637265  19 KLRKPMVEKIRRERINSSIEKLKTLLAQEFV---KQQPdsRQEKADILEMTLDFLRRSQKS 76
Cdd:cd11462    2 KLLKPLVEKRRRDRINRSLEELRVLLLQNTQdekLKNP--KVEKAEILELTVQFLRNSSLS 60

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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 238637265  19 KLRKPMVEKIRRERINSSIEKLKTLLAQEFVKQQPD-SRQEKADILEMTLDFLRRSQKSS 77
Cdd:cd11463    6 KTLKPLMEKRRRARINESLNQLKTLILPLVGKDSSRySKLEKADILEMTVRFLQDLPASS 65

basic helix-loop-helix-orange (bHLH-O) domain found in hairy and enhancer of split HES-1, HES-4 and similar proteins; The family includes two bHLH-O transcriptional repressors, HES-1 and HES-4. HES-1, also termed Class B basic helix-loop-helix protein 39 (bHLHb39), or hairy homolog, or hairy-like protein (HL), plays an essential role in development of both compartment and boundary cells of the central nervous system. It regulates the maintenance of neural stem/progenitor cells by inhibiting proneural gene expression via Notch signaling. HES-4, also termed Class B basic helix-loop-helix protein 42 (bHLHb42), or bHLH factor Hes4, antagonizes the function of Twist-1 to regulate lineage commitment of bone marrow stromal/stem cells (BMSC). Epigenetic dysregulation of HES-4 is associated with striatal degeneration in postmortem Huntington brains. Both HES-1 and HES-4 are mammalian counterparts 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 238637265  17 TNKLRKPMVEKIRRERINSSIEKLKTLLAQEFVKQQPD-SRQEKADILEMTLDFLRRSQK 75
Cdd:cd11459    2 HRKSSKPIMEKRRRARINESLSQLKTLILDALKKDSSRhSKLEKADILEMTVKHLRNLQR 61

Helix-loop-helix DNA-binding domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 238637265   19 KLRKPMVEKIRRERINSSIEKLKTLLaqefVKQQPDSRQEKADILEMTLDFLRRSQ 74
Cdd:pfam00010   2 REAHNERERRRRDRINDAFDELRELL----PTLPPDKKLSKAEILRLAIEYIKHLQ 53

basic helix-loop-helix-orange (bHLH-O) domain found in Drosophila melanogaster protein hairy, protein deadpan and similar proteins; Protein hairy is a bHLH transcriptional repressor of genes that require a bHLH-O protein for their transcription. It acts as a pair-rule protein that regulates embryonic segmentation and adult bristle patterning. Protein deadpan is closely related to the product of the segmentation gene hairy. It is a direct target of Notch signaling and regulates neuroblast self-renewal in Drosophila.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 238637265  19 KLRKPMVEKIRRERINSSIEKLKTLLAQEFVKQQP-DSRQEKADILEMTLDFLRRSQKSSAA 79
Cdd:cd18913    4 KSSKPIMEKRRRARINASLNELKSLLLDALKKDGTrHSKLEKADILEMTVKHLRQVQRQQLA 65

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        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 238637265   3 PTITGSISSRetlltnKLRKPMVEKIRRERINSSIEKLKTLLAQEFVKQQpDSRQEKADILEMTLDFLRRSQKSSAAG 80
Cdd:cd18920    1 PTTTSQIMAR------KKRRGIIEKRRRDRINNSLSELRRLVPTAFEKQG-SAKLEKAEILQMTVDHLKMLQATGGKG 71

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        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 238637265  19 KLRKPMVEKIRRERINSSIEKLKTLLAqEFVKQQPDSRQEKADILEMTLDFLRRSQ 74
Cdd:cd18916    1 KSKKPMLERQRRARINKCLSELKTLVA-ECSGDDGCLRMDKAEMLETAVAFMRQQQ 55

helix loop helix domain;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 238637265    23 PMVEKIRRERINSSIEKLKTLLAQEfvkqQPDSRQEKADILEMTLDFLRRSQK 75
Cdd:smart00353   1 NARERRRRRKINEAFDELRSLLPTL----PKNKKLSKAEILRLAIEYIKSLQE 49

basic helix-loop-helix-orange (bHLH-O) domain found in HERP/HES-like family; The HERP/HES-like family includes bHLH-O transcriptional regulators that are related to the Drosophila hairy and Enhancer-of-split (HES) proteins. The HERP (HES-related repressor protein) subfamily proteins 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. Hairy and enhancer of split (HES)-related repressor protein (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 subfamily. It is involved in the regulation of Drosophila circadian rhythms. It functions as both an activator and a repressor of clock gene expression. The HES subfamily proteins contain a basic helix-loop-helix (bHLH) domain with an invariant proline residue in its basic region, an orange domain in the central region and a conserved tetrapeptide motif, WRPW, at its C-terminal region. They form heterodimers or homodimers via their HLH domain and bind DNA to repress gene transcription that play an essential role in development of both compartment and boundary cells of the central nervous system.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 238637265  25 VEKIRRERINSSIEKLKTLLAqEFVKQQPDSRQEKADILEMTLDFLRRSQK 75
Cdd:cd19685    1 SEKRRRQRINDKLNQLKELLP-PNLSKQSRSKLSKAEILEMAITELRRLQQ 50

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in the microphthalmia-associated transcription factor family (MITF) family; The MITF (also known as microphthalmia-TFE, or MiT) family is a small family that contain a basic helix loop helix domain associated with a leucine zipper (bHLHZip). The MITF family 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 family can form homodimers or heterodimers with each other but not with other bHLH or bHLHzip proteins.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 238637265  24 MVEKIRRERINSSIEKLKTLLAQEFVkqqPDSRQEKADILEMTLDFLRRSQK 75
Cdd:cd11397   11 MIERRRRFNINDRIKELGTLLPKSND---PDMRWNKGTILKASVDYIRKLQK 59

basic helix-loop-helix (bHLH) domain found in the spermatogenesis- and oogenesis-specific basic helix-loop-helix-containing protein (SOHLH) family; 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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*.
gi 238637265  26 EKIRRERINSSIEKLKTLLAQeFVKQQPDsrqeKADILEMTLDFLR 71
Cdd:cd18908   10 ERLRRERIKSSCDQLRDLLPY-IKGRKLD----MASVLEMTVKYIR 50

basic helix-loop-helix-orange (bHLH-O) domain found in differentially expressed in chondrocytes protein 1 (DEC1) and similar proteins; DEC1, also termed Class E basic helix-loop-helix protein 40 (bHLHe40), or Class B basic helix-loop-helix protein 2 (bHLHb2), or enhancer-of-split and hairy-related protein 2 (SHARP-2), or stimulated by retinoic acid gene 13 protein (STRA13), is a bHLH-O transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 238637265   7 GSISSRETLLTNKLRKPMVEKIRRERINSSIEKLKTLLAqEFVKQQPDSRQEKADILEMTLDFLR 71
Cdd:cd19749    3 GLKRSEDSKDTYKLPHRLIEKKRRDRINECIAQLKDLLP-EHLKLTTLGHLEKAVVLELTLKHVK 66

basic helix-loop-helix (bHLH) domain found in Saccharomyces cerevisiae phosphate system positive regulatory protein PHO4 and similar proteins; PHO4 is a transcriptional activator that regulates the expression of repressible phosphatase under phosphate starvation conditions in Saccharomyces cerevisiae. The PHO4 protein has four functional domains with the bHLH domain at its carboxyl-terminal region. It regulates transcription by binding to promoter of the genes as a homodimer.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 238637265  26 EKIRRERINSSIEKLKTLLAQEFVKQQPDSR-----------------QEKADILEMTLDFLRRSQK 75
Cdd:cd11392   10 ERGRRDRLNAALKELASLMPAEFVEGKMGADgsasdsndkekaaasaaGSKAATVEMAIDYIKHLQK 76

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in upstream stimulatory factors, USF1, USF2 and similar proteins; Upstream stimulatory factor 1 and 2 (USF-1 and USF-2) are members of bHLHzip transcription factor family. 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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 238637265  25 VEKIRRERINSSIEKLKTLL---AQEFVKQQpdsrQEKADILEMTLDFLR 71
Cdd:cd11396    5 VERRRRDKINNWIVKLAKIVpdcEKDNSKQG----QSKGGILSKACDYIQ 50