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 61098067  10 AAELRKNLKPLLEKRRRARINESLSQLKGLVLPLLGAETSRSSKLEKADILEMTVRFLQEQPAT 73
Cdd:cd11463   1 ASELRKTLKPLMEKRRRARINESLNQLKTLILPLVGKDSSRYSKLEKADILEMTVRFLQDLPAS 64

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 61098067  10 AAELRKNLKPLLEKRRRARINESLSQLKGLVLPLLGAETSRSSKLEKADILEMTVRFLQEQPAT 73
Cdd:cd11463   1 ASELRKTLKPLMEKRRRARINESLNQLKTLILPLVGKDSSRYSKLEKADILEMTVRFLQDLPAS 64

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

                           10        20        30
                   ....*....|....*....|....*....|....*....
gi 61098067     85 SYLEGYRACLARLARVLPACSVLEPAVSARLLEHLRQRT 123
Cdd:smart00511   2 SFRSGYRECANEVSRFLSQLPGTDPDVRARLLSHLQTHL 40

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 61098067    85 SYLEGYRACLARLARVLPACSVLEPAVSARLLEHLRQR 122
Cdd:pfam07527   1 RFRAGFNECANEVSRFLSTLEGVDPDLRQRLLNHLQRC 38

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 61098067  10 AAELRKNLKPLLEKRRRARINESLSQLKGLVLPLLGAETSRSSKLEKADILEMTVRFLQEQPAT 73
Cdd:cd11463   1 ASELRKTLKPLMEKRRRARINESLNQLKTLILPLVGKDSSRYSKLEKADILEMTVRFLQDLPAS 64

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
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 61098067  12 ELRKNLKPLLEKRRRARINESLSQLKGLVLPLLGAETSRSSKLEKADILEMTVRFLQE 69
Cdd:cd11459   1 EHRKSSKPIMEKRRRARINESLSQLKTLILDALKKDSSRHSKLEKADILEMTVKHLRN 58

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        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 61098067  14 RKNLKPLLEKRRRARINESLSQLKGLVLPLLGAETSRSSKLEKADILEMTVRFLQEQ 70
Cdd:cd19741   8 RKVTKPLLERKRRARINKCLDELKDLMVEALATEAENVSKLEKADILELTVRHLKKL 64

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 61098067  18 KPLLEKRRRARINESLSQLKglvlPLLGAETSR---SSKLEKADILEMTVRFLQEQPA 72
Cdd:cd11461   4 KPVVEKTRRDRINSSIEQLK----TLLEKEFQRhqpNSKLEKADILEMTVSFLKQSAK 57

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
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 61098067  14 RKNLKPLLEKRRRARINESLSQLKGLVLPLLgaETSRSSKLEKADILEMTVRFLQEQPAT 73
Cdd:cd11447   9 RKKRRGIIEKRRRDRINSSLSELRRLVPTAF--EKQGSSKLEKAEILQMTVDHLKMLHAT 66

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 61098067  15 KNLKPLLEKRRRARINESLSQLKGLVLPLLGAETsrSSKLEKADILEMTVRFLQEQ 70
Cdd:cd18916   1 KSKKPMLERQRRARINKCLSELKTLVAECSGDDG--CLRMDKAEMLETAVAFMRQQ 54

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
                ....*....|....*....|....*....|....*....|....*.
gi 61098067  22 EKRRRARINESLSQLKGLVLPLLgaETSRSSKLEKADILEMTVRFL 67
Cdd:cd19685   2 EKRRRQRINDKLNQLKELLPPNL--SKQSRSKLSKAEILEMAITEL 45

Helix-loop-helix DNA-binding domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 61098067    14 RKNLKPLLEKRRRARINESLSQLKGLVLPLlgaetSRSSKLEKADILEMTVRFLQE 69
Cdd:pfam00010   1 RREAHNERERRRRDRINDAFDELRELLPTL-----PPDKKLSKAEILRLAIEYIKH 51

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

                           10        20        30
                   ....*....|....*....|....*....|....*....
gi 61098067     85 SYLEGYRACLARLARVLPACSVLEPAVSARLLEHLRQRT 123
Cdd:smart00511   2 SFRSGYRECANEVSRFLSQLPGTDPDVRARLLSHLQTHL 40

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
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 61098067  14 RKNLKPLLEKRRRARINESLSQLKGLVLPLLgaETSRSSKLEKADILEMTVRFLQEQPAT 73
Cdd:cd18920  10 RKKRRGIIEKRRRDRINNSLSELRRLVPTAF--EKQGSAKLEKAEILQMTVDHLKMLQAT 67

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 61098067    85 SYLEGYRACLARLARVLPACSVLEPAVSARLLEHLRQR 122
Cdd:pfam07527   1 RFRAGFNECANEVSRFLSTLEGVDPDLRQRLLNHLQRC 38

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 61098067   5 RRVEDAAELRKNLKPLLEKRRRARINESLSQLKGLVLPLLGAETsrSSKLEKADILEMTVRFLQ 68
Cdd:cd19749   5 KRSEDSKDTYKLPHRLIEKKRRDRINECIAQLKDLLPEHLKLTT--LGHLEKAVVLELTLKHVK 66

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
                ....*....|....*....|....*....|....*....|....*....
gi 61098067  20 LLEKRRRARINESLSQLKGLVLPLLGAETsrSSKLEKADILEMTVRFLQ 68
Cdd:cd11409  10 LIEKKRRDRINECIAQLKDLLPEHLKLTT--LGHLEKAVVLELTLKHLK 56

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 61098067  22 EKRRRARINESLSQLKGLVlPLLGAETsrssklEKADILEMTVRFL 67
Cdd:cd19683  10 ERQRRERIKIACDQLRKLV-PGCSRKT------DKATVFEFTVAYI 48

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 61098067  22 EKRRRARINESLSQLKGLVLPLLGAETsrSSKLEKADILEMTVRFLQE 69
Cdd:cd11387   6 ERRRRDNINEKIQELGSLVPPSRLETK--DLKPNKGSILSKAVEYIRE 51

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in protein Max and similar proteins; Max, also termed Class D basic helix-loop-helix protein 4 (bHLHd4), or Myc-associated factor X, is a bHLHZip transcription regulator that forms a sequence-specific DNA-binding protein complex with MYC or MAD which recognizes the core sequence 5'-CAC[GA]TG-3'. The MYC:MAX complex is a transcriptional activator, whereas the MAD:MAX complex is a transcriptional repressor. Max homodimer bind DNA but is transcriptionally inactive. Targeted deletion of max results in early embryonic lethality in mice.

                        10        20        30
                ....*....|....*....|....*....|....*..
gi 61098067  21 LEKRRRARINESLSQLKGLVLPLLGAETSRSSKLEKA 57
Cdd:cd11406   8 LERKRRDHIKDSFHSLRDSVPSLQGEKASRAQILKKA 44