basic Helix-Loop-Helix-zipper (bHLHzip) domain found in upstream stimulatory factor 1 (USF1) and similar proteins; USF1, also termed Class B basic helix-loop-helix protein 11 (bHLHb11), or major late transcription factor 1, 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. It is ubiquitously expressed and involved in the transcription activation of various functional genes implicated in lipid and glucose metabolism, stress response, immune response, cell cycle control and tumour suppression. USF-1 recruits chromatin remodeling enzymes and interact with co-activators and the members of the transcription pre-initiation complex. Genetic polymorphisms of USF1 are associated with some metabolic and cardiovascular diseases, like diabetes, atherosclerosis, coronary artery calcifications and familial combined hyperlipidaemia (FCHL).

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2507987638 196 RDEKRRAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKSGQSKGGILSKACDYIQELRQSNHR 260
Cdd:cd18924     1 RDEKRRAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKSGQSKGGILSKACDYIQELRQSNHR 65

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in upstream stimulatory factor 1 (USF1) and similar proteins; USF1, also termed Class B basic helix-loop-helix protein 11 (bHLHb11), or major late transcription factor 1, 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. It is ubiquitously expressed and involved in the transcription activation of various functional genes implicated in lipid and glucose metabolism, stress response, immune response, cell cycle control and tumour suppression. USF-1 recruits chromatin remodeling enzymes and interact with co-activators and the members of the transcription pre-initiation complex. Genetic polymorphisms of USF1 are associated with some metabolic and cardiovascular diseases, like diabetes, atherosclerosis, coronary artery calcifications and familial combined hyperlipidaemia (FCHL).

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2507987638 196 RDEKRRAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKSGQSKGGILSKACDYIQELRQSNHR 260
Cdd:cd18924     1 RDEKRRAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKSGQSKGGILSKACDYIQELRQSNHR 65

helix loop helix domain;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 2507987638  205 NEVERRRRDKINNWIVQLSKIIPDCSmESTKsgQSKGGILSKACDYIQELRQSNH 259
Cdd:smart00353   1 NARERRRRRKINEAFDELRSLLPTLP-KNKK--LSKAEILRLAIEYIKSLQEELQ 52

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in upstream stimulatory factor 1 (USF1) and similar proteins; USF1, also termed Class B basic helix-loop-helix protein 11 (bHLHb11), or major late transcription factor 1, 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. It is ubiquitously expressed and involved in the transcription activation of various functional genes implicated in lipid and glucose metabolism, stress response, immune response, cell cycle control and tumour suppression. USF-1 recruits chromatin remodeling enzymes and interact with co-activators and the members of the transcription pre-initiation complex. Genetic polymorphisms of USF1 are associated with some metabolic and cardiovascular diseases, like diabetes, atherosclerosis, coronary artery calcifications and familial combined hyperlipidaemia (FCHL).

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2507987638 196 RDEKRRAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKSGQSKGGILSKACDYIQELRQSNHR 260
Cdd:cd18924     1 RDEKRRAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKSGQSKGGILSKACDYIQELRQSNHR 65

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 2507987638 203 QHNEVERRRRDKINNWIVQLSKIIPDCSMESTKSGQSKGGILSKACDYIQELRQSNHR 260
Cdd:cd11396     1 THNEVERRRRDKINNWIVKLAKIVPDCEKDNSKQGQSKGGILSKACDYIQELRSQNER 58

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 2507987638 196 RDEKRRAQHNEVERRRRDKINNWIVQLSKIIPDCSmestKSGQSKGGILSKACDYIQELRQSNHRL 261
Cdd:cd18910     1 RREKKRESHNEVERRRKDKINAGINKIGELLPDRD----AKKQSKNMILEQAYKYIVELKKKNDKL 62

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in sterol regulatory element-binding protein (SREBP) family; 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.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2507987638 200 RRAQHNEVERRRRDKINNWIVQLSKII--PDCSMestksgqSKGGILSKACDYIQELRQSNHRLSEELQGL 268
Cdd:cd11394     6 KRSAHNAIEKRYRSSINDRIIELKDLVvgPDAKM-------NKSAVLRKAIDYIRYLQKVNQKLKQENMAL 69

Helix-loop-helix DNA-binding domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2507987638 200 RRAQHNEVERRRRDKINNWIVQLSKIIPdCSMESTKsgQSKGGILSKACDYIQELR 255
Cdd:pfam00010   1 RREAHNERERRRRDRINDAFDELRELLP-TLPPDKK--LSKAEILRLAIEYIKHLQ 53

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 2507987638 200 RRAQHNEVERRRRDKINNWIVQLSKIIPDcsMEStKSGQSKGGILSKACDYIQELRQSNHRLSEElqgLDQLQLDNDVLR 279
Cdd:cd11400     1 KRRLHNVLERQRRNDLKNSFEKLRDLVPE--LAD-NEKASKVVILKKATEYIKQLQQEEKKLEKE---KDKLKARNEQLR 74

                  ....*.
gi 2507987638 280 QQVEDL 285
Cdd:cd11400    75 KKLERL 80

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 2507987638 208 ERRRRDKINNWIVQLSKIIPDCsmeSTKSGQSKGGILSKACDYIQELRQ 256
Cdd:cd00083     1 ERRRRDKINDAFEELKRLLPEL---PDSKKLSKASILQKAVEYIRELQS 46

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        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2507987638 200 RRAQHNEVERRRRDKINNWIVQLSKIIPdcSMESTKsgQSKGGILSKACDYIQELRQSNHrlseelqgldqlqldndVLR 279
Cdd:cd11406     1 KRAHHNALERKRRDHIKDSFHSLRDSVP--SLQGEK--ASRAQILKKATEYIQYMRRKNH-----------------THQ 59

                          90
                  ....*....|
gi 2507987638 280 QQVEDLKNKN 289
Cdd:cd11406    60 QDIDDLKRQN 69

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 2507987638 196 RDEKRRAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKsgQSKGGILSKACDYIQELR--QSNHRLSEE 264
Cdd:cd11397     1 KDRQKKDNHNMIERRRRFNINDRIKELGTLLPKSNDPDMR--WNKGTILKASVDYIRKLQkeQERLRQLEE 69

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in microphthalmia-associated transcription factor (MITF) and similar proteins; MITF, also termed Class E basic helix-loop-helix protein 32 (bHLHe32), is a bHLHzip transcription factor that is involved in neural crest melanocytes development as well as the pigmented retinal epithelium. It regulates the expression of genes with essential roles in cell differentiation, proliferation and survival. It binds to M-boxes (5'-TCATGTG-3') and symmetrical DNA sequences (E-boxes) (5'-CACGTG-3') found in the promoters of target genes, such as BCL2 and tyrosinase (TYR).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2507987638 188 KSEAPRTTRDEKRRAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKsgQSKGGILSKACDYIQELRQSNHRLSEelqg 267
Cdd:cd18926     1 ESEARALAKERQKKDNHNLIERRRRFNINDRIKELGTLIPKSNDPDMR--WNKGTILKASVDYIRKLQREQQRAKE---- 74

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 2507987638 268 ldqlqLDNdvlRQQVEDLKNKNLLLRAQ-----LRHHG 300
Cdd:cd18926    75 -----LEN---RQKKLEHANRHLLLRIQelemqARAHG 104

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 2507987638 198 EKRRAqHNEVERRRRDKINNWIVQLSKIIPDCSMESTKSGQ-----------------SKGGILSKACDYIQELRQSNHR 260
Cdd:cd11399     2 SKKTA-HNMIEKRYRSNINDRIAELRDSVPALREAYKSARGededeedlggltpatklNKATILSKATEYIRHLEKKNKR 80

                  ....*...
gi 2507987638 261 LSEELQGL 268
Cdd:cd11399    81 LSRENASL 88

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 2507987638 198 EKRRAQHNEVERRRRDKINNWIVQLSKIIPdcSMESTKSGQ-SKGGILSKACDYIQELRQSNHRLSEELQGLDQ 270
Cdd:cd11405     1 EQRRLSHISAEQKRRFNIKSGFDTLQSLIP--SLGQNPNQKvSKAAMLQKAAEYIKSLKRERQQMQEEAEQLRQ 72

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in transcription factor E3 (TFE3) and similar proteins; TFE3, also termed Class E basic helix-loop-helix protein 33 (bHLHe33), is a bHLHzip transcription factor that is involved in B cell function. 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 TFEB or MITF.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2507987638 190 EAPRTTRDEKRRAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKsgQSKGGILSKACDYIQELRQSNHRlSEELQgld 269
Cdd:cd18928     1 EAKAFLKERQKKDNHNLIERRRRFNINDRIKELGTLIPKSTDPEMR--WNKGTILKASVDYIRKLQKEQQR-SKEIE--- 74

                          90       100
                  ....*....|....*....|....
gi 2507987638 270 qlqldndvLRQQVEDLKNKNLLLR 293
Cdd:cd18928    75 --------MRQRKLEQANRSLQLR 90

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
                  ....*....|....*....|....*....|....*....|....*....|....
gi 2507987638 204 HNEVERRRRDKINNWIVQLSKIIPDCSMESTKSGQSKGGILSKACDYIQELRQS 257
Cdd:cd11389     1 HKVIEKRRRDRINESLAELRRLVPEARKSKGSGKLEKAEILEMTLQHLKALQSS 54

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in Schizosaccharomyces pombe ESC1 (spESC1) and similar proteins; spESC1 is a bHLHzip protein with homology to human MyoD and Myf-5 myogenic differentiation inducers. It is involved in the sexual differentiation process.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2507987638 201 RAQHNEVERRRRDKINNWIVQLSKIIPDcsMESTKSgqSKGGILSKACDYIQELRQSNHRLSEELQGLD 269
Cdd:cd19690     1 RVSHKLAERKRRKEMKELFEDLRDALPQ--ERGTKA--SKWEILTKAISYIQQLKRHIRELRSEVNDLR 65

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 2507987638 208 ERRRRDKINNWIVQLSKIIPdcsmESTKsgQSKGGILSKACDYIQELRQSNHRLSEELQGL 268
Cdd:cd11443     7 ERRRRKKLNDRLYMLRSVVP----KITK--MDRASILGDAIDYVKELLQEINELQDELEGL 61

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        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2507987638 200 RRAQHNEVERRRRDKINNWIVQLSKIIPDcsmesTKSGQSKGGILSKACDYIQELRQSNHRLSEELQGLDQ 270
Cdd:cd11453     3 PRSKHSATEQRRRSKINERLQALRDLIPH-----SDQKRDKASFLLEVIEYIQALQEKVAKLEEQVQGWGG 68

basic helix-loop-helix (bHLH) domain found in Arabidopsis thaliana genes coding transcription factors and similar proteins; bHLH proteins are the second largest class of plant transcription factors that regulate transcription of genes that are involve in many essential physiological and developmental process. bHLH proteins are transcriptional regulators that are found in organisms from yeast to humans. The Arabidopsis bHLH proteins that have been characterized so far have roles in regulation of fruit dehiscence, cell development (carpel, anther and epidermal), phytochrome signaling, flavonoid biosynthesis, hormone signaling and stress responses.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 2507987638 204 HNEVERRRRDKINNWIVQLSKIIPDCsmesTKSGQSKggILSKACDYIQELRQSNHRLS 262
Cdd:cd11393     1 HSIAERKRREKINERIRALRSLVPNG----GKTDKAS--ILDEAIEYIKFLQEQVKVLS 53

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 2507987638 207 VERRRRDKINNWIVQLSKIIPDCSMESTKSGQSKGGILSKACDYIQELRQSN 258
Cdd:cd19685     1 SEKRRRQRINDKLNQLKELLPPNLSKQSRSKLSKAEILEMAITELRRLQQEV 52

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 2507987638 204 HNEVERRRRDKINNWIVQLSKIIPDCSMESTKSGQSKGGILSKACDYIQELRQSN 258
Cdd:cd11408     2 HKVIEKRRRDRINRCLNELGKTVPMALAKQTSGKLEKAEILEMTVQYLRALHSAD 56

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 2507987638 196 RDEKRRAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKsgQSKGGILSKACDYIQELRQSNHRLSEelqgldqlqLDN 275
Cdd:cd18925     1 KERQKKDNHNLIERRRRYNINYRIKELGTLIPKSNDPDMR--WNKGTILKASVEYIKWLQKEQQRARE---------LEH 69

                          90
                  ....*....|....*...
gi 2507987638 276 dvlRQQVEDLKNKNLLLR 293
Cdd:cd18925    70 ---RQKKLEQANRRLLLR 84

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in Max-interacting protein 1 (MXI1) and similar proteins; MXI1, also termed Max interactor 1, or Class C basic helix-loop-helix protein 11 (bHLHc11), is a bHLHZip transcriptional repressor that binds with MAX to form a sequence-specific DNA-binding protein complex which recognizes the core sequence 5'-CAC[GA]TG-3'. It thus antagonizes MYC transcriptional activity by competing for MAX. It plays an important role in the regulation of cell proliferation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2507987638 201 RAQHNEVERRRRDKINNWIVQLSKIIPdcsMESTKSGQSKGGILSKACDYIQELRQSNHRlseELQGLDQLQLDNDVLRQ 280
Cdd:cd18930     2 RSTHNELEKNRRAHLRLCLERLKVLIP---LGPDCTRHTTLGLLNKAKAHIKKLEEADRK---SQHQLENLEREQRFLKR 75

                  ....*
gi 2507987638 281 QVEDL 285
Cdd:cd18930    76 RLEQL 80

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 2507987638 200 RRAQHNEVERRRRDKINNWIVQLSKIIPDCSMEStksgQSKGGILSKACDYIQELRQSNHRL 261
Cdd:cd11419     4 RREIANSNERRRMQSINAGFQSLRTLLPHCDGEK----LSKAAILQQTAEYIFSLEQEKTRL 61

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        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 2507987638 199 KRRAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKSgqskgGILSKACDYIQELR 255
Cdd:cd19683     1 KSRERHNAKERQRRERIKIACDQLRKLVPGCSRKTDKA-----TVFEFTVAYIKFLR 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2507987638 192 PRTTRDEKRRAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKSGQSKGGILSKACDYIQEL 254
Cdd:cd11447     1 TTSSQIQARKKRRGIIEKRRRDRINSSLSELRRLVPTAFEKQGSSKLEKAEILQMTVDHLKML 63

basic Helix-Loop-Helix (bHLH) domain found in Arabidopsis thaliana MYC1 and similar proteins; MYC1, also termed AtbHLH12, or EN 58, acts as a transcription activator, when associated with MYB75/PAP1 or MYB90/PAP2.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2507987638 204 HNEVERRRRDKINNWIVQLSKIIPDCSMESTKSgqskggILSKACDYIQELRqsnhRLSEELQGL 268
Cdd:cd18918     1 LFATERERREKLNEKFSDLRNLIPNPTKNDRAS------ILSDAIKYINELQ----RTVEELKSL 55

basic helix-loop-helix (bHLH) domain found in Arabidopsis thaliana protein AIG1 and similar proteins; AIG1, also termed AtbHLH32, or EN 54, or protein target of MOOPTEROS 5, is a transcription factor required for MONOPTEROS-dependent root initiation in embryo.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2507987638 204 HNEVERRRRDKINNWIVQLSKIIPDcsmeSTKsgQSKGGILSKACDYIQELRQ 256
Cdd:cd11455    11 HSEAERRRRERINSHLATLRTLLPN----LSK--TDKASLLAEVVQHVKELKR 57

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in Circadian locomotor output cycles protein kaput (CLOCK) and similar proteins; CLOCK, also termed Class E basic helix-loop-helix protein 8 (bHLHe8), is a bHLH-PAS transcriptional activator which forms a core component of the circadian clock. It forms heterodimers with another bHLH-PAS protein, Brain-Muscle-Arnt-Like (also known as BMAL or ARNT3 or mop3), which regulates circadian rhythm. BMAL1-CLOCK heterodimer complex activates transcription from E-box (CANNTG) elements found in the promoter of circadian responsive genes.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2507987638 196 RDEKRRAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKSgqskgGILSKACDYIQELRQ 256
Cdd:cd19734     3 KDKAKRVSRNKSEKKRRDQFNVLIKELGSMLPGNARKMDKS-----TVLQKSIDFLRKHKE 58

basic helix-loop-helix (bHLH) domain found in achaete-scute complex-like (ASCL) family; The achaete-scute complex-like (ASCL, also known as achaete-scute complex homolog or ASH) family of bHLH transcription factors, ASCL1-5, have been implicated in cell fate specification and differentiation. They are critical for proper development of the nervous system. The deregulation of ASCL plays a key role in psychiatric and neurological disorders. ASCL-1, also termed Class A basic helix-loop-helix protein 46 (bHLHa46), or achaete-scute homolog 1 (ASH-1), or mammalian achaete-scute homolog 1 (Mash1), is a neural-specific bHLH transcription factor that is expressed in subsets of neural progenitors in both the central and peripheral nervous system. It plays a key role in neuronal differentiation and specification in the nervous system. ASCL-2, also termed achaete-scute homolog 2 (ASH-2), or Class A basic helix-loop-helix protein 45 (bHLHa45), or mammalian achaete-scute homolog 2 (Mash2), is a bHLH transcription factor that is involved in Schwann cell differentiation and control of proliferation in adult peripheral nerves. ASCL-3, also termed Class A basic helix-loop-helix protein 42 (bHLHa42), or bHLH transcriptional regulator Sgn-1, or achaete-scute homolog 3 (ASH-3), is a bHLH transcription factor specifically localized in the duct cells of the salivary glands. It may act as transcriptional repressor that inhibits myogenesis. The family also includes Drosophila melanogaster achaete-scute complex (AS-C) proteins, which consists of lethal of scute (also known as achaete-scute complex protein T3 or AST3), scute (also known as achaete-scute complex protein T4 or AST4), achaete (also known as achaete-scute complex protein T5 or AST5), and asense (also known as achaete-scute complex protein T8 or AST8). They are involved in the determination of the neuronal precursors in the peripheral nervous system and the central nervous system, as well as in sex determination and dosage compensation.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 2507987638 200 RRAQHNEVERRRRDKINNWIVQLSKIIPDCSmESTKSgqSKGGILSKACDYIQELRQ 256
Cdd:cd11418     1 RVARRNERERRRVQAVNDAFDRLRQHVPYLK-RRKKL--SKVKTLRRAIEYIRHLQK 54

basic helix-loop-helix (bHLH) domain found in Arabidopsis thaliana protein transparent testa 8 (TT8) and similar proteins; The family includes several bHLH transcription factors from Arabidopsis thaliana, such as TT8, EGL1, and GL3. TT8, also termed AtbHLH42, or EN 32, is involved in the control of flavonoid pigmentation and plays a key role in regulating leucoanthocyanidin reductase (BANYULS) and dihydroflavonol-4-reductase (DFR). EGL1, also termed AtbHLH2, or EN 30, or AtMYC146, or protein enhancer of GLABRA 3, is involved in epidermal cell fate specification and regulates negatively stomata formation but promotes trichome formation. GL3, also termed AtbHLH1, or AtMYC6, or protein shapeshifter, or EN 31, is involved in epidermal cell fate specification. It regulates negatively stomata formation, but, in association with TTG1 and MYB0/GL1, promotes trichome formation, branching and endoreplication.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2507987638 204 HNEVERRRRDKINNWIVQLSKIIPDCSMestksgQSKGGILSKACDYIQELRQSNHRL 261
Cdd:cd11451     6 HAMAERRRREKLNERFITLRSMVPFVTK------MDKVSILGDAIEYLKQLQRRVEEL 57

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in c-Myc and similar proteins; c-Myc, also termed Myc proto-oncogene protein, or Class E basic helix-loop-helix protein 39 (bHLHe39), or transcription factor p64, a bHLHZip proto-oncogene protein that functions as a transcription factor, which binds DNA in a non-specific manner, yet also specifically recognizes the core sequence 5'-CAC[GA]TG-3'. It activates the transcription of growth-related genes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2507987638 197 DEKRRAqHNEVERRRRDKINNWIVQLSKIIPDCsmeSTKSGQSKGGILSKACDYIQELRQSNHRLSEElqgLDQLQLDND 276
Cdd:cd11458     3 NDKRRT-HNVLERQRRNELKLSFFALRDQIPEV---ANNEKAPKVVILKKATEYILSMQADEQRLISE---KEQLRRRRE 75

                  ....*....
gi 2507987638 277 VLRQQVEDL 285
Cdd:cd11458    76 QLKHRLEQL 84

basic helix-loop-helix (bHLH) domain found in Arabidopsis thaliana OBP3-responsive gene 2 (ORG2), 3 (ORG3) and similar proteins; The family includes ORG2 (also termed AtbHLH38, or EN 8) and ORG3 (also termed AtbHLH39, or EN 9), both of which act as bHLH transcription factors.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2507987638 200 RRAQHNEVERRRRDKINNWIVQLSKIIPdcsMESTKSGQSKGGILSKACDYIQELRQSNHRLSEE 264
Cdd:cd18914     1 KKLLHNDVERQRRQEMASLFSSLRSLLP---LQYIKGKLSVSDHVDEAVNYIKELQEKIKELSEK 62

basic Helix-Loop-Helix (bHLH) domain found in Saccharomyces cerevisiae INO4 and similar proteins; INO4 is a bHLH transcriptional activator of phospholipid synthetic genes (such as INO1, CHO1/PSS, CHO2/PEM1, OPI3/PEM2, etc.). It is required for de-repression of phospholipid biosynthetic gene expression in response to inositol deprivation in yeast. INO4 dimerizes with INO2 and binds to an UAS DNA element to control expression of the genes whose expression is inositol-responsive.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2507987638 200 RRAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKsgqSKGGILSKACDYIQELRQSNHRLSEEL 265
Cdd:cd11403     2 KKENHISSEHKRREAIREGFDRLCAIVPALSSSQSR---SEAVVYVKTVEYLKELYERRAKLRSQL 64

basic helix-loop-helix (bHLH) domain found in 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
                  ....*....|....*....|....*....|....*...
gi 2507987638 199 KRRAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKS 236
Cdd:cd18909     1 QRRERHNRMERDRRRRIRICCDELNLLVPFCNAETDKA 38

basic helix-loop-helix-orange (bHLH-O) domain found in differentially expressed in chondrocytes protein 2 (DEC2) and similar proteins; DEC2, also termed Class E basic helix-loop-helix protein 41 (bHLHe41), or Class B basic helix-loop-helix protein 3 (bHLHb3), or enhancer-of-split and hairy-related protein 1 (SHARP-1), 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
                  ....*....|....*....|....*....|....*....|..
gi 2507987638 187 PKSEAPRTTRDEKRRAQHNEVERRRRDKINNWIVQLSKIIPD 228
Cdd:cd19750     2 PKRGLKRDESKEAYKLPHRLIEKKRRDRINECIAQLKDLLPE 43

basic helix-loop-helix (bHLH) domain found in Arabidopsis thaliana protein IAA-leucine resistant 3 (ILR3) and similar proteins; ILR3, also termed AtbHLH105, or EN 133, is a bHLH transcription factor that plays a role in resistance to amide-linked indole-3-acetic acid (IAA) conjugates such as IAA-Leu and IAA-Phe. It may regulate gene expression in response to metal homeostasis changes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2507987638 208 ERRRRDKINNWIVQLSKII-PDcsmESTKSGqsKGGILSKACDYIQELRQSNHRLSEElqgldqlqldNDVLRQQVEDLK 286
Cdd:cd11446     5 EKLRRDKLNERFMELSNVLePG---RPPKTD--KATILGDAIRMLKQLRGEVQKLKEE----------NSSLQEESKELK 69

                          90
                  ....*....|.
gi 2507987638 287 nknlLLRAQLR 297
Cdd:cd11446    70 ----AEKNELR 76