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        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 386763488 504 KDRQKKDNHNMIERRRRFNINDRIKELGTLLPKGSDafyevvRDIRPNKGTILKSSVDYIKCLKHEVTRLRQNE 577
Cdd:cd11397    1 KDRQKKDNHNMIERRRRFNINDRIKELGTLLPKSND------PDMRWNKGTILKASVDYIRKLQKEQERLRQLE 68

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        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 386763488 504 KDRQKKDNHNMIERRRRFNINDRIKELGTLLPKGSDafyevvRDIRPNKGTILKSSVDYIKCLKHEVTRLRQNE 577
Cdd:cd11397    1 KDRQKKDNHNMIERRRRFNINDRIKELGTLLPKSND------PDMRWNKGTILKASVDYIRKLQKEQERLRQLE 68

MITF/TFEB/TFEC/TFE3 N-terminus; This domain is found at the N-terminus of several transcription factors including microphthalmia-associated transcription factor, transcription factor EB, transcription factor EC and transcription factor E3.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 386763488  272 VPPQVLQVSTVLENPTRYHVIQKQKNQVRQYLSESFKPSM 311
Cdd:pfam15951  55 VPVEVLKVQTHLENPTKYHIQQAQRQQVKQYLSTTYGAKQ 94

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        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 386763488 504 KDRQKKDNHNMIERRRRFNINDRIKELGTLLPKGSDafyevvRDIRPNKGTILKSSVDYIKCLKHEVTRLRQNE 577
Cdd:cd11397    1 KDRQKKDNHNMIERRRRFNINDRIKELGTLLPKSND------PDMRWNKGTILKASVDYIRKLQKEQERLRQLE 68

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in transcription factor EB (TFEB) and similar proteins; TFEB, also termed Class E basic helix-loop-helix protein 35 (bHLHe35), is a bHLHzip transcription factor that is required for vascularization of the mouse placenta. It specifically recognizes and binds E-box sequences (5'-CANNTG-3'). Its efficient DNA-binding requires dimerization with itself or with another MiT/TFE family member such as TFE3 or MITF.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763488 498 EMNALAKDRQKKDNHNMIERRRRFNINDRIKELGTLLPKGSDAfyevvrDIRPNKGTILKSSVDYIKCLKHEVTRLRQNE 577
Cdd:cd18927    1 EARALAKERQKKDNHNLIERRRRFNINDRIKELGTLIPKTNDL------DVRWNKGTILKASVDYIKRMQKDLQRSRELE 74

                         90
                 ....*....|....*..
gi 386763488 578 LRQRQVELQNRKLMSRI 594
Cdd:cd18927   75 NHSRRLEMTNKQLWLRI 91

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in transcription factor EC (TFEC) and similar proteins; TFEC, also termed Class E basic helix-loop-helix protein 34 (bHLHe34), or transcription factor EC-like (TFEC-L), is a bHLHzip transcriptional regulator that acts as a repressor or an activator and regulates gene expression in macrophages. It plays an important role in the niche to expand hematopoietic progenitors through the modulation of several cytokines.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763488 504 KDRQKKDNHNMIERRRRFNINDRIKELGTLLPKGSDAfyevvrDIRPNKGTILKSSVDYIKCLKHEVTRLRQNELRQRQV 583
Cdd:cd18925    1 KERQKKDNHNLIERRRRYNINYRIKELGTLIPKSNDP------DMRWNKGTILKASVEYIKWLQKEQQRARELEHRQKKL 74

                         90
                 ....*....|.
gi 386763488 584 ELQNRKLMSRI 594
Cdd:cd18925   75 EQANRRLLLRI 85

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in Saccharomyces cerevisiae centromere-binding protein 1 (CBP-1) and similar proteins; CBP-1, also termed centromere promoter factor 1 (CPF1), or centromere-binding factor 1 (CBF1), is a bHLHzip protein that is required for chromosome stability and methionine prototrophy. It binds as a homodimer to the centromere DNA elements I (CDEI, GTCACATG) region of the centromere that is required for optimal centromere function.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763488 506 RQKKDNHNMIERRRRFNINDRIKELGTLLPKGSDAFyevvrdirpNKGTILKSSVDYIKCLKHEVTRLRQnelRQRQVEL 585
Cdd:cd11398    5 RQRRDNHKEVERRRRENINEGINELAALVPGNAREK---------NKGAILARAVEYIQELQETEAKNIE---KWTLEKL 72

                         90
                 ....*....|....*..
gi 386763488 586 QNRKLMSRIKELEMQAK 602
Cdd:cd11398   73 LTDQAIAELAALNEKLR 89

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in sterol regulatory element-binding protein (SREBP) family and similar proteins; The SREBP family includes SREBP1 and SREBP2, which are bHLHzip transcriptional activator of genes encoding proteins essential for cholesterol biosynthesis/uptake and fatty acid biosynthesis. SREBP1 and SREBP2 are principally found in the liver and in adipocytes and made up of an N-terminal transcription factor portion (composed of an activation domain, a bHLHzip domain, and a nuclear localization signal), a hydrophobic region containing two membrane spanning regions, and a C-terminal regulatory segment. They recognize a symmetric sterol regulatory element (TCACNCCAC) instead of E-box. The family also includes Saccharomyces cerevisiae transcription factor HMS1 (also termed high-copy MEP suppressor protein 1) and serine-rich protein TYE7. HMS1 is a putative bHLHzip transcription factor involved in exit from mitosis and pseudohyphal differentiation. TYE7, also termed basic-helix-loop-helix protein SGC1, is a putative bHLHzip transcription activator required for Ty1-mediated glycolytic gene expression. TYE7 N-terminal is extremely rich in serine residues. It binds DNA on E-box motifs, 5'-CANNTG-3'. TYE7 is not essential for growth.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763488 506 RQKKDNHNMIERRRRFNINDRIKELGTLLPK--------GSDAFYEVVRDIRPNKGTILKSSVDYIKCLKHEVTRL--RQ 575
Cdd:cd11395    1 PRKRLPHNAIEKRYRSNLNTKIERLRDAIPSlrspegksDDGGLGGLAPTTKLSKATILTKAIEYIRHLEQENERLeeEN 80

                 ....*.
gi 386763488 576 NELRQR 581
Cdd:cd11395   81 EELRQQ 86

helix loop helix domain;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 386763488   513 NMIERRRRFNINDRIKELGTLLPKGSDafyevvrDIRPNKGTILKSSVDYIKCLKHEV 570
Cdd:smart00353   1 NARERRRRRKINEAFDELRSLLPTLPK-------NKKLSKAEILRLAIEYIKSLQEEL 51

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in Saccharomyces cerevisiae transcription factor HMS1 and similar proteins; HMS1, also termed high-copy MEP suppressor protein 1, is a putative bHLHzip transcription factor involved in exit from mitosis and pseudohyphal differentiation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763488 506 RQKKDNHNMIERRRRFNINDRIKELGTLLPKGSDAFYEVVRD-------------IRPNKGTILKSSVDYIKCLKHevtr 572
Cdd:cd11399    1 PSKKTAHNMIEKRYRSNINDRIAELRDSVPALREAYKSARGEdedeedlggltpaTKLNKATILSKATEYIRHLEK---- 76

                         90
                 ....*....|....*.
gi 386763488 573 lRQNELRQRQVELQNR 588
Cdd:cd11399   77 -KNKRLSRENASLRER 91

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in sterol regulatory element-binding protein 2 (SREBP2) and similar proteins; SREBP2, also termed Class D basic helix-loop-helix protein 2 (bHLHd2), or sterol regulatory element-binding transcription factor 2 (SREBF2), is a member of a family of bHLHzip transcription factors that recognize sterol regulatory element 1 (SRE-1). It acts as a transcription activator of cholesterol biosynthesis.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 386763488 504 KDRQKKDNHNMIERRRRFNINDRIKELGTLLpKGSDAfyevvrdiRPNKGTILKSSVDYIKCLKHEVTRLRQNEL 578
Cdd:cd18922    2 KEGERRTTHNIIEKRYRSSINDKIIELKDLV-MGTDA--------KMHKSGVLRKAIDYIKYLQQVNHKLRQENM 67

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
                 ....*....|....*....|....*....|....*....|....*....|..
gi 386763488 516 ERRRRFNINDRIKELGTLLPKGSDAFyevvrdiRPNKGTILKSSVDYIKCLK 567
Cdd:cd00083    1 ERRRRDKINDAFEELKRLLPELPDSK-------KLSKASILQKAVEYIRELQ 45

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        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 386763488 506 RQKKDNHNMIERRRRFNINDRIKELGTLLPKGSDAfyevvRDIRPNKGTILKSSVDYIKCLKHEVTRLR--QNELRQR 581
Cdd:cd11405    1 EQRRLSHISAEQKRRFNIKSGFDTLQSLIPSLGQN-----PNQKVSKAAMLQKAAEYIKSLKRERQQMQeeAEQLRQE 73

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in upstream stimulatory factor 2 (USF2) and similar proteins; USF2, also termed Class B basic helix-loop-helix protein 12 (bHLHb12), or major late transcription factor 2, or FOS-interacting protein (FIP), or upstream transcription factor 2, is a bHLHzip transcription factor that binds to a symmetrical DNA sequence (E-boxes) (5'-CACGTG-3') that is found in a variety of viral and cellular promoters.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 386763488 504 KDRQKKDNHNMIERRRRFNINDRIKELGTLLPkgsDAFYEVVRdIRPNKGTILKSSVDYIKCLKHEVTRLRQN 576
Cdd:cd18923    4 RDERRRAQHNEVERRRRDKINNWIVQLSKIIP---DCNTDNSK-TGASKGGILSKACDYIRELRQTNQRMQET 72

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in the Myc family; The Myc family is a member of the bHLHzip family of transcription factors that play important roles in the control of normal cell proliferation, growth, survival and differentiation. All Myc isoforms contain two independently functioning polypeptide chain regions: N-terminal transactivating residues and a C-terminal bHLHzip segment. The bHLHzip family of bHLH transcription factors are characterized by a highly conserved N-terminal basic region that may bind DNA at a consensus hexanucleotide sequence known as the E-box (CANNTG) followed by HLH and leucine zipper motifs that may interact with other proteins to form homo- and heterodimers. Myc heterodimerizes with Max enabling specific binding to E-box DNA sequences in the promoters of target genes. The Myc proto-oncoprotein family includes at least five different functional members: c-, N-, L-, S- and B-Myc (which is lacking the bHLH domain).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763488 508 KKDNHNMIERRRRFNINDRIKELGTLLPkgsdafyEVVRDIRPNKGTILKSSVDYIKCLKHEVTRL--RQNELRQRQVEL 585
Cdd:cd11400    1 KRRLHNVLERQRRNDLKNSFEKLRDLVP-------ELADNEKASKVVILKKATEYIKQLQQEEKKLekEKDKLKARNEQL 73

                 ....*..
gi 386763488 586 QnRKLMS 592
Cdd:cd11400   74 R-KKLER 79

basic helix-loop-helix (bHLH) domain found in Arabidopsis thaliana BES1-interacting Myc-like proteins (BIMs) and similar proteins; The family includes Arabidopsis thaliana BIM1 and its homologs (BIM2 and BIM3), which are bHLH transcription factors that interact with BES1 to regulate transcription of Brassinosteroid (BR)-induced gene. BR regulates many growth and developmental processes such as cell elongation, vascular development, senescence stress responses, and photomorphogenesis. BIM1 heterodimerize with BES1 and bind to E-box sequences present in many BR-induced promoters to regulated BR-induced genes.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 386763488 512 HNMIERRRRFNINDRIKELGTLLPKGSDafyevvrdiRPNKGTILKSSVDYIKCLKHEVTRLR 574
Cdd:cd11453    7 HSATEQRRRSKINERLQALRDLIPHSDQ---------KRDKASFLLEVIEYIQALQEKVAKLE 60

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in basic helix-loop-helix domain-containing protein USF3 and similar proteins; USF3, also termed upstream transcription factor 3, is a bHLHzip protein that is involved in the negative regulation of epithelial-mesenchymal transition, the process by which epithelial cells lose their polarity and adhesion properties to become mesenchymal cells with enhanced migration and invasive properties.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 386763488 508 KKDNHNMIERRRRFNINDRIKELGTLLPKgsdafyevVRDIRPNKGTILKSSVDYIKCLKHEVTRLRQN 576
Cdd:cd18910    5 KRESHNEVERRRKDKINAGINKIGELLPD--------RDAKKQSKNMILEQAYKYIVELKKKNDKLLLN 65

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in L-Myc and similar proteins; L-Myc, also termed Class E basic helix-loop-helix protein 38 (bHLHe38), or protein L-Myc-1, or V-myc myelocytomatosis viral oncogene homolog, is a bHLHZip oncoprotein belonging to the Myc oncogene protein family. It binds DNA as a heterodimer with MAX. L-Myc is co-expressed with another Myc family member and has weaker transformation/transactivation activities. L-Myc knockout mouse did not exhibit any phenotypic abnormalities.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 386763488 505 DRQKKDNHNMIERRRRFNINDRIKELGTLLPkgsdafyEVVRDIRPNKGTILKSSVDYIKCLkheVTRLRQNELRQRQVE 584
Cdd:cd11457    4 DVAKRKNHNFLERKRRNDLRSRFLALRDEVP-------GLASCSKTPKVVILSKATEYLRGL---VSAERRMAAEKRQLK 73

                         90
                 ....*....|....
gi 386763488 585 LQNRKLMSRIKELE 598
Cdd:cd11457   74 SRQQQLLRRIAQLK 87

basic helix-loop-helix (bHLH) domain found in Arabidopsis thaliana protein aborted microspores (AMS) and similar proteins; The family includes several bHLH transcription factors from Arabidopsis thaliana, such as AMS, ICE1 and SCREAM2. AMS, also termed AtbHLH21, or EN 48, plays a crucial role in tapetum development and it is required for male fertility and pollen differentiation. ICE1, also termed inducer of CBF expression 1, or AtbHLH116, or EN 45, or SCREAM, acts as a transcriptional activator that regulates the cold-induced transcription of CBF/DREB1 genes. It binds specifically to the MYC recognition sites (5'-CANNTG-3') found in the CBF3/DREB1A promoter. SCREAM2, also termed AtbHLH33, or EN 44, mediates stomatal differentiation in the epidermis probably by controlling successive roles of SPCH, MUTE, and FAMA.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 386763488 514 MIERRRRFNINDRIKELGTLLPKGSdafyevvrdiRPNKGTILKSSVDYIKCLKHEVTRLrQNEL 578
Cdd:cd11443    5 MAERRRRKKLNDRLYMLRSVVPKIT----------KMDRASILGDAIDYVKELLQEINEL-QDEL 58

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        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 386763488 509 KDNHNMIERRRRFNINDRIKELGTLLPkgsdafYEVVRDIRPNKGTILKSSVDYIKCLK 567
Cdd:cd11391    1 REKSREAAKKRRDKENAEISELASLLP------LPPAVGSKLDKLSVLRLAVAYLRLKK 53

basic helix-loop-helix (bHLH) domain found in Arabidopsis thaliana protein maternal effect embryo arrest 8 (AtMEE8) and similar proteins; AtMEE8, also termed AtbHLH108, or EN 132, is a bHLH transcription factor required during early embryo development, for the endosperm formation.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 386763488 512 HNMIERRRRFNINDRIKELGTLLPKGSDafyevvrdiRPNKGTILKSSVDYIKCLKHEVTRLRQ 575
Cdd:cd19698    1 HNLLEKKRRERIKDKIEILKGLTPNCTP---------KSDIASILSCVIDYIKSLLLQVEKLSM 55

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 386763488 515 IERRRRFNINDRIKELGTLLPKGSdafyEVVRDIRPNKGTILKSSVDYIKCLKHEV 570
Cdd:cd19685    1 SEKRRRQRINDKLNQLKELLPPNL----SKQSRSKLSKAEILEMAITELRRLQQEV 52

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in transcription factor AP-4 (TFAP4) and similar proteins; TFAP4, also termed activating enhancer-binding protein 4, or Class C basic helix-loop-helix protein 41 (bHLHc41), is a bHLHzip transcription factor that activates both viral and cellular genes involved in the regulation of cellular proliferation, stemness, and epithelial-mesenchymal transition by binding to the symmetrical DNA sequence 5'-CAGCTG-3'.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 386763488 513 NMIERRRRFNINDRIKELGTLLPKGSDAfyevvrdiRPNKGTILKSSVDYIKCLKHEVTRL 573
Cdd:cd11419    9 NSNERRRMQSINAGFQSLRTLLPHCDGE--------KLSKAAILQQTAEYIFSLEQEKTRL 61

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in circadian clock protein PASD1; PASD1, also termed PAS domain-containing protein 1, is evolutionarily related to Circadian locomotor output cycles protein kaput (CLOCK)and functions as a suppressor of the biological clock that drives the daily circadian rhythms of cells throughout the body. Mammalian PASD1 doesn't harbor the bHLH-PAS domain and is not included in this family.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 386763488 499 MNALAKDRQKKDNHNMIERRRRFNINDRIKELGTLLpKGSDafyevvRDIRPNKGTILKSSVDYIK 564
Cdd:cd19736    1 MDEDEKDRAKRASRNKSEKKRRDQFNVLIKELCTML-QGHG------HPLKMDKSTILQRTIDFLQ 59

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 386763488 508 KKDNHNMIERRRRFNINDRIKELGTLLPkgsdAFYEVVRDIRPNKGTILKSSVDYIKCLK 567
Cdd:cd11407    1 RKKRRGIIEKRRRDRINNSLAELRRLVP----TAFEKQGSAKLEKAEILQMTVDHLKMLH 56

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 386763488 508 KKDNHNMIERRRRFNINDRIKELGTLLPkgsdAFYEVVRDIRPNKGTILKSSVDYIKCL 566
Cdd:cd19748    9 RKRRRGIIEKRRRDRINNSLSELRRLVP----SAFEKQGSAKLEKAEILQMTVDHLKML 63

basic helix-loop-helix (bHLH) domain found in Arabidopsis thaliana ILI1-BINDING BHLH 1 (IBH1) and similar proteins; The family includes several bHLH transcription factors from Arabidopsis thaliana, such as IBH1, UPBEAT1, PAR1 and PAR2. IBH1, also termed bHLH zeta, or AtbHLH158, is an atypical and probable non DNA-binding bHLH transcription factor that acts as transcriptional repressor that negatively regulates cell and organ elongation in response to gibberellin (GA) and brassinosteroid (BR) signaling. IBH1 forms heterodimer with BHLH49, thus inhibiting DNA binding of BHLH49, which is a transcriptional activator that regulates the expression of a subset of genes involved in cell expansion by binding to the G-box motif. UPBEAT1, also termed AtbHLH151, or EN 146, is a bHLH transcription factor that modulates the balance between cellular proliferation and differentiation in root growth. It does not act through cytokinin and auxin signaling, but by repressing peroxidase expression in the elongation zone. PAR1 (also termed AtbHLH165, or protein helix-loop-helix 1, or protein phytochrome rapidly regulated 1) and PAR2 (also termed AtbHLH166, or protein helix-loop-helix 2, or protein phytochrome rapidly regulated 2) are two atypical bHLH transcription factors that act as negative regulators of a variety of shade avoidance syndrome (SAS) responses, including seedling elongation and photosynthetic pigment accumulation. They act as direct transcriptional repressor of two auxin-responsive genes, SAUR15 and SAUR68. They may function in integrating shade and hormone transcriptional networks in response to light and auxin changes.

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gi 386763488 516 ERRRRFNINDRIKELGTLLPKGSDAFyevvrdirpNKGTILKSSVDYIKCLKHEVTRLR 574
Cdd:cd11444    5 RRRGEEAIERRLRALRRLVPGGRESM---------EVEELLQETADYIMFLEMQVKVMK 54