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 1958770437  87 IREAHSQTEKRRRDKMNHLIWKLSSMIPPHIPTAHKLDKLSILRRAVQYLRSQRGMTEFY 146
Cdd:cd11469     1 FREAHSQTEKRRRDKMNNLIEELSAMIPQCNPMARKLDKLTVLRMAVQHLKSLKGSTSSF 60

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in aryl hydrocarbon receptor nuclear translocator-like protein 2 (ARNTL2) and similar proteins; ARNTL2, also termed Basic-helix-loop-helix-PAS protein MOP9, or brain and muscle ARNT-like 2 (BMAL2), or CYCLE-like factor (CLIF), or Class E basic helix-loop-helix protein 6 (bHLHe6), or member of PAS protein 9, or PAS domain-containing protein 9 (PASD9), is a neuronal bHLH-PAS transcriptional factor, regulating cell cycle progression and preventing cell death, whose sustained expression might ensure brain neuron survival. It also plays important roles in tumor angiogenesis. ARNT-2 heterodimerize with other bHLH-PAS proteins such as aryl hydrocarbon receptor (AhR), hypoxia-inducible factor (HIF), and single-minded (SIM).

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958770437  87 IREAHSQTEKRRRDKMNHLIWKLSSMIPPHIPTAHKLDKLSILRRAVQYLRSQRGMTEFY 146
Cdd:cd11469     1 FREAHSQTEKRRRDKMNNLIEELSAMIPQCNPMARKLDKLTVLRMAVQHLKSLKGSTSSF 60

Helix-loop-helix DNA-binding domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1958770437  88 REAHSQTEKRRRDKMNHLIWKLSSMIPPHIPTAhKLDKLSILRRAVQYLRS 138
Cdd:pfam00010   2 REAHNERERRRRDRINDAFDELRELLPTLPPDK-KLSKAEILRLAIEYIKH 51

PAS domain; PAS motifs appear in archaea, eubacteria and eukarya. Probably the most surprising identification of a PAS domain was that in EAG-like K+-channels.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 1958770437  349 EFITRFAMNGKFVYVDQRATAILGYLPQELLGTSCYEYFHQDDHSNLSDKHKAVLQ 404
Cdd:smart00091  12 DGIFVLDLDGRILYANPAAEELLGYSPEELIGKSLLELIHPEDRERVQEALQRLLS 67

PAS domain; PAS motifs appear in archaea, eubacteria and eukarya. Probably the most surprising identification of a PAS domain was that in EAG-like K+-channels. PAS domains have been found to bind ligands, and to act as sensors for light and oxygen in signal transduction.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958770437 171 GFLLVVgCEGGRILFVSKSVSKTLHYDQASLMGQNLFDFLQPKDVAKVKEQLSCDVSLR-----EKPIGTKTSPQVHSHS 245
Cdd:cd00130     3 DGVIVL-DLDGRILYANPAAEQLLGYSPEELIGKSLLDLIHPEDREELRERLENLLSGGepvtlEVRLRRKDGSVIWVLV 81

                          90
                  ....*....|....*
gi 1958770437 246 HIGRSRVHSGSRRSF 260
Cdd:cd00130    82 SLTPIRDEGGEVIGL 96

PAS fold; The PAS fold corresponds to the structural domain that has previously been defined as PAS and PAC motifs. The PAS fold appears in archaea, eubacteria and eukarya. This domain can bind gases (O2, CO and NO), FAD, 4-hydroxycinnamic acid and NAD+ (Matilla et.al., FEMS Microbiology Reviews, fuab043, 45, 2021, 1. https://doi.org/10.1093/femsre/fuab043).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958770437 179 EGGRILFVSKSVSKTLHYDQASLMGQNLFDFLQPKDVAKVKEQLSCDVSLREKPIGTKTSPQVHSHSHI------GRSRV 252
Cdd:pfam00989  19 EDGRILYVNAAAEELLGLSREEVIGKSLLDLIPEEDDAEVAELLRQALLQGEESRGFEVSFRVPDGRPRhvevraSPVRD 98

                          90
                  ....*....|...
gi 1958770437 253 HSGSRRSFFFRMK 265
Cdd:pfam00989  99 AGGEILGFLGVLR 111

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in aryl hydrocarbon receptor nuclear translocator-like protein 2 (ARNTL2) and similar proteins; ARNTL2, also termed Basic-helix-loop-helix-PAS protein MOP9, or brain and muscle ARNT-like 2 (BMAL2), or CYCLE-like factor (CLIF), or Class E basic helix-loop-helix protein 6 (bHLHe6), or member of PAS protein 9, or PAS domain-containing protein 9 (PASD9), is a neuronal bHLH-PAS transcriptional factor, regulating cell cycle progression and preventing cell death, whose sustained expression might ensure brain neuron survival. It also plays important roles in tumor angiogenesis. ARNT-2 heterodimerize with other bHLH-PAS proteins such as aryl hydrocarbon receptor (AhR), hypoxia-inducible factor (HIF), and single-minded (SIM).

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958770437  87 IREAHSQTEKRRRDKMNHLIWKLSSMIPPHIPTAHKLDKLSILRRAVQYLRSQRGMTEFY 146
Cdd:cd11469     1 FREAHSQTEKRRRDKMNNLIEELSAMIPQCNPMARKLDKLTVLRMAVQHLKSLKGSTSSF 60

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in aryl hydrocarbon receptor nuclear translocator (ARNT) family; The ARNT family of bHLH-PAS transcription regulators includes ARNT, ARNT-like proteins (ARNTL and ARNTL2), and Drosophila melanogaster protein cycle. They act as the heterodimeric partner for bHLH-PAS proteins such as aryl hydrocarbon receptor (AhR), hypoxia-inducible factor (HIF), and single-minded (SIM). These bHLH-PAS transcription complexes are involved in transcriptional responses to xenobiotic, hypoxia, and developmental pathways. Heterodimerization of bHLH-PAS proteins with ARNT is mediated by contacts between both the bHLH and the tandem PAS domains. ARNT use bHLH and/or PAS domains to interact with several transcriptional coactivators. It is required for activity of the aryl hydrocarbon (dioxin) receptor. ARNTL, also termed Basic-helix-loop-helix-PAS protein MOP3, or brain and muscle ARNT-like 1 (BMAL1), or Class E basic helix-loop-helix protein 5 (bHLHe5), or member of PAS protein 3, or PAS domain-containing protein 3 (PASD3), or bHLH-PAS protein JAP3, is a member of the bHLH-PAS transcription factor family that forms heterodimers with another bHLH-PAS protein, CLOCK (circadian locomotor output cycle kaput), which regulates circadian rhythm. ARNTL-CLOCK heterodimer complex activates transcription from E-box (CANNTG) elements found in the promoter of circadian responsive genes. ARNTL is highly homologous to ARNT. ARNTL2, also termed Basic-helix-loop-helix-PAS protein MOP9, or brain and muscle ARNT-like 2 (BMAL2), or CYCLE-like factor (CLIF), or Class E basic helix-loop-helix protein 6 (bHLHe6), or member of PAS protein 9, or PAS domain-containing protein 9 (PASD9), is a neuronal bHLH-PAS transcriptional factor, regulating cell cycle progression and preventing cell death, whose sustained expression might ensure brain neuron survival. It also plays important roles in tumor angiogenesis. Protein cycle, also termed brain and muscle ARNT-like 1 (BMAL1), or MOP3, is a putative bHLH-PAS transcription factor involved in the generation of biological rhythms in Drosophila. It activates cycling transcription of Period (PER) and Timeless (TIM) by binding to the E-box (5'-CACGTG-3') present in their promoters.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1958770437  88 REAHSQTEKRRRDKMNHLIWKLSSMIPPHIPTAHKLDKLSILRRAVQYLRSQRGMT 143
Cdd:cd11437     2 RSNHSEIEKRRRDKMNAYIQELSALVPACNAMSRKLDKLTVLRMAVQHLKSLRGTG 57

PAS domain; PAS motifs appear in archaea, eubacteria and eukarya. Probably the most surprising identification of a PAS domain was that in EAG-like K+-channels. PAS domains have been found to bind ligands, and to act as sensors for light and oxygen in signal transduction.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958770437 348 AEFITRFAMNGKFVYVDQRATAILGYLPQELLGTSCYEYFHQDDHSNLSDKHKAVLQsKEKILTDSYKFRVKDGSFVTLK 427
Cdd:cd00130     2 PDGVIVLDLDGRILYANPAAEQLLGYSPEELIGKSLLDLIHPEDREELRERLENLLS-GGEPVTLEVRLRRKDGSVIWVL 80

                          90       100
                  ....*....|....*....|
gi 1958770437 428 SKWFSFTNPWTKKLEYIVSV 447
Cdd:cd00130    81 VSLTPIRDEGGEVIGLLGVV 100

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 1958770437  88 REAHSQTEKRRRDKMNHLIWKLSSMIPPHIPTAHKLDKLSILRRAVQYLRSQRG 141
Cdd:cd11391     1 REKSREAAKKRRDKENAEISELASLLPLPPAVGSKLDKLSVLRLAVAYLRLKKF 54

helix loop helix domain;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 1958770437   95 EKRRRDKMNHLIWKLSSMIPPHiPTAHKLDKLSILRRAVQYLRSQRGMTE 144
Cdd:smart00353   4 ERRRRRKINEAFDELRSLLPTL-PKNKKLSKAEILRLAIEYIKSLQEELQ 52

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in Circadian locomotor output cycles protein kaput (CLOCK) and similar proteins; The family includes CLOCK, neuronal PAS domain-containing protein 2 (NPAS2) and non-mammalian circadian clock protein PASD1. CLOCK, also termed Class E basic helix-loop-helix protein 8 (bHLHe8), is a transcriptional activator which forms a core component of the circadian clock. NPAS2, also termed neuronal PAS2, or basic-helix-loop-helix-PAS protein MOP4, or Class E basic helix-loop-helix protein 9 (bHLHe9), or member of PAS protein 4, or PAS domain-containing protein 4, is a transcriptional activator which forms a core component of the circadian clock. PASD1 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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1958770437  88 REAHSQTEKRRRDKMNHLIWKLSSMIPPHiptAHKLDKLSILRRAVQYLRSQRGMT 143
Cdd:cd11441     1 RKSRNLSEKKRRDQFNVLINELASMLPGR---GRKMDKSTVLKKTIAFLRKHKELT 53

PAS fold; The PAS fold corresponds to the structural domain that has previously been defined as PAS and PAC motifs. The PAS fold appears in archaea, eubacteria and eukarya.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958770437 360 FVYVDQRATAILGYLPQELLGT--SCYEYFHQDDHSNLSDKHKAVLQSKEKILTDsYKFRVKDGSFVTLKSKWFSFTNpW 437
Cdd:pfam08447   1 IIYWSPRFEEILGYTPEELLGKgeSWLDLVHPDDRERVREALWEALKGGEPYSGE-YRIRRKDGEYRWVEARARPIRD-E 78

                          90
                  ....*....|.
gi 1958770437 438 TKKLEYIVSVN 448
Cdd:pfam08447  79 NGKPVRVIGVA 89

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 1958770437  91 HSQTEKRRRDKMNHLIWKLSSMIPPH--IPTAHKLDKLSILRRAVQYLR 137
Cdd:cd11387     2 HNAVERRRRDNINEKIQELGSLVPPSrlETKDLKPNKGSILSKAVEYIR 50

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in Drosophila melanogaster Circadian locomotor output cycles protein kaput (dCLOCK) and similar proteins; dCLOCK, also termed dPAS1, is a bHLH-PAS Circadian regulator that acts as a transcription factor and generates a rhythmic output with a period of about 24 hours.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1958770437  88 REAHSQTEKRRRDKMNHLIWKLSSMIPphiPTAHKLDKLSILRRAVQYLRSQRGMT----EFYLGENAKPSFI 156
Cdd:cd19735    11 RKSRNLSEKKRRDQFNVLINELCSMVS---TSNRKMDKSTVLKSTIAFLKNHNEVTmqshQQEIQEDWKPSFL 80

basic helix-loop-helix (bHLH) domain found in Arabidopsis thaliana phytochrome interacting factors (PIFs) and similar proteins; The family includes several bHLH transcription factors from Arabidopsis thaliana, such as PIFs, ALC, PIL1, SPATULA, and UNE10. PIFs (PIF1, PIF3, PIF4, PIF5, PIF6 and PIF7) have been shown to control light-regulated gene expression. They directly bind to the photoactivated phytochromes and are degraded in response to light signals. ALC, also termed AtbHLH73, or protein ALCATRAZ, or EN 98, is required for the dehiscence of fruit, especially for the separation of the valve cells from the replum. It promotes the differentiation of a strip of labile non-lignified cells sandwiched between layers of lignified cells. PIL1, also termed AtbHLH124, or protein phytochrome interacting factor 3-like 1, or EN 110, is involved in responses to transient and long-term shade. It is required for the light-mediated inhibition of hypocotyl elongation and necessary for rapid light-induced expression of the photomorphogenesis- and circadian-related gene APRR9. PIL1 seems to play a role in multiple PHYB responses, such as flowering transition and petiole elongation. SPATULA, also termed AtbHLH24, or EN 99, plays a role in floral organogenesis. It promotes the growth of carpel margins and of pollen tract tissues derived from them. UNE10, also termed AtbHLH16, or protein UNFERTILIZED EMBRYO SAC 10, or EN 99, is required during the fertilization of ovules by pollen.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1958770437  89 EAHSQTEKRRRDKMNHLIWKLSSMipphIPTAHKLDKLSILRRAVQYLRS 138
Cdd:cd11445     4 EVHNLSERRRRDRINEKMKALQEL----IPNCNKTDKASMLDEAIEYLKS 49

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 1958770437  90 AHSQTEKRRRDKMNHLIWKLSSMIPPHIP--TAHKLDKLSILRRAVQYLRS 138
Cdd:cd11408     1 SHKVIEKRRRDRINRCLNELGKTVPMALAkqTSGKLEKAEILEMTVQYLRA 51

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
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1958770437  88 REAHSQTEKRRRDKMNHLIWKLSSMIPPHiptAHKLDKLSILRRAVQYLRSQRGMT 143
Cdd:cd19734     8 RVSRNKSEKKRRDQFNVLIKELGSMLPGN---ARKMDKSTVLQKSIDFLRKHKEIT 60

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in the aryl hydrocarbon receptor (AhR) family; The AhR family includes AhR, AhR repressor (AhRR) and Drosophila melanogaster protein spineless. AhR, also termed Ah receptor, or Dioxin receptor (DR), or Class E basic helix-loop-helix protein 76 (bHLHe76), is the only member of bHLH-PAS transcription regulators that bind and be activated by small chemical ligands. It is activated by Dioxin to control the expression of certain genes to influence biological processes such as apoptosis, proliferation, cell growth and differentiation. To form active DNA binding complexes AhR dimerizes with a bHLH-PAS factor ARNT (Aryl hydrocarbon Nuclear Receptor Translocator). AhRR, also termed Class E basic helix-loop-helix protein 77 (bHLHe77), is a member of bHLH-PAS transcription factors that acts as a negative regulator of AhR, playing key roles in development and environmental sensing. AhRR functions by competing with AhR for its partner ARNT. AhRR-ARNT complexes are transcriptionally inactive. Spineless is a bHLH-PAS transcription factor that plays an important role in fly morphogenesis. It is both necessary and sufficient for the formation of the ommatidial mosaic.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1958770437  96 KRRRDKMNHLIWKLSSMIPPHIPTAHKLDKLSILRRAVQYLRSQ 139
Cdd:cd19696     9 KRHRDRLNSELDELASLLPFPEDVISKLDKLSVLRLSVSYLRTK 52

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
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1958770437  88 REAHSQTEKRRRDKMNHLIWKLSSMIPPHiPTAHKLDKLSILRRAVQYLRSQRGMT 143
Cdd:cd19736    11 RASRNKSEKKRRDQFNVLIKELCTMLQGH-GHPLKMDKSTILQRTIDFLQKQKEIT 65

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
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1958770437  91 HSQTEKRRRDKMNHLIWKLSSMipphIPTAHKLDKLSILRRAVQYLRS-QRGMTEFYL 147
Cdd:cd18918     1 LFATERERREKLNEKFSDLRNL----IPNPTKNDRASILSDAIKYINElQRTVEELKS 54

PAS domain; PAS motifs appear in archaea, eubacteria and eukarya. Probably the most surprising identification of a PAS domain was that in EAG-like K+-channels. PAS domains have been found to bind ligands, and to act as sensors for light and oxygen in signal transduction.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958770437 171 GFLLVVgCEGGRILFVSKSVSKTLHYDQASLMGQNLFDFLQPKDVAKVKEQLSCDVSLR-----EKPIGTKTSPQVHSHS 245
Cdd:cd00130     3 DGVIVL-DLDGRILYANPAAEQLLGYSPEELIGKSLLDLIHPEDREELRERLENLLSGGepvtlEVRLRRKDGSVIWVLV 81

                          90
                  ....*....|....*
gi 1958770437 246 HIGRSRVHSGSRRSF 260
Cdd:cd00130    82 SLTPIRDEGGEVIGL 96

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in Drosophila melanogaster protein spineless and similar proteins; Spineless is a bHLH-PAS transcription factor that plays an important role in fly morphogenesis. It is both necessary and sufficient for the formation of the ommatidial mosaic.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1958770437  92 SQTEKRRRDKMNHLIWKLSSMIPPHIPTAHKLDKLSILRRAVQYLRSQ 139
Cdd:cd19730     8 SNPSKRHRERLNAELDHLASLLPFEQSVISKLDKLSILRLSVSYLRTK 55

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
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1958770437  88 REAHSQTEKRRRDKMNHLIWKLSSMIPPHIPTAHKL--DKLSILRRAVQYLRSQR 140
Cdd:cd18924     6 RAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKSgqSKGGILSKACDYIQELR 60

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1958770437  88 REAHSQTEKRRRDKMNHLIWKLSSMIPPHIPTAHKL--DKLSILRRAVQYLRSQRgMTEFYLGENAK 152
Cdd:cd18923     9 RAQHNEVERRRRDKINNWIVQLSKIIPDCNTDNSKTgaSKGGILSKACDYIRELR-QTNQRMQETYK 74

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in neuronal PAS domain-containing protein 2 (NPAS2) and similar proteins; NPAS2, also termed neuronal PAS2, or basic-helix-loop-helix-PAS protein MOP4, or Class E basic helix-loop-helix protein 9 (bHLHe9), or member of PAS protein 4, or PAS domain-containing protein 4 (PASD4), is a bHLH-PAS transcriptional activator which forms a core component of the circadian clock.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1958770437  88 REAHSQTEKRRRDKMNHLIWKLSSMIPPHiptAHKLDKLSILRRAVQYLRSQ 139
Cdd:cd19737    11 RASRNKSEKKRRDQFNVLIKELSSMLPGN---TRKMDKTTVLEKVIGFLQKH 59

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 1958770437  94 TEKRRRDKMNHLIWKLSSMIPP--HIPTAHKLDKLSILRRAVQYLR 137
Cdd:cd19685     1 SEKRRRQRINDKLNQLKELLPPnlSKQSRSKLSKAEILEMAITELR 46

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in sterol regulatory element-binding protein 1 (SREBP1) and similar proteins; SREBP1, also termed Class D basic helix-loop-helix protein 1 (bHLHd1), or sterol regulatory element-binding transcription factor 1 (SREBF1), is a member of a family of bHLHzip transcription factors that recognize sterol regulatory element 1 (SRE-1). It acts as a transcriptional activator required for lipid homeostasis. It may control transcription of the low-density lipoprotein receptor gene as well as the fatty acid. SREBP1 has dual sequence specificity binding to both an E-box motif (5'-ATCACGTGA-3') and to SRE-1 (5'-ATCACCCCAC-3').

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1958770437  88 REAHSQTEKRRRDKMNHLIWKLSSMIpphIPTAHKLDKLSILRRAVQYLR 137
Cdd:cd18921     7 RTAHNAIEKRYRSSINDKIIELKDLV---VGTEAKLNKSAVLRKAIDYIR 53

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 1958770437  93 QTEKRRRDKMNHLIWKLSSMIPPHIPTAH---KLDKLSILRRAVQYLRSQRGMT 143
Cdd:cd11461     6 VVEKTRRDRINSSIEQLKTLLEKEFQRHQpnsKLEKADILEMTVSFLKQSAKLS 59

PAS domain S-box; The PAS domain was previously described. This sensory box, or S-box domain occupies the central portion of the PAS domain but is more widely distributed. It is often tandemly repeated. Known prosthetic groups bound in the S-box domain include heme in the oxygen sensor FixL, FAD in the redox potential sensor NifL, and a 4-hydroxycinnamyl chromophore in photoactive yellow protein. Proteins containing the domain often contain other regulatory domains such as response regulator or sensor histidine kinase domains. Other S-box proteins include phytochromes and the aryl hydrocarbon receptor nuclear translocator. [Regulatory functions, Small molecule interactions]

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1958770437 357 NGKFVYVDQRATAILGYLPQELLGTSCYEYFHQDDHSNLSDKHKAVLQSKEKILTDSYKFRVKDGS 422
Cdd:TIGR00229  22 EGNILYVNPAFEEIFGYSAEELIGRNVLELIPEEDREEVRERIERRLEGEPEPVSEERRVRRKDGS 87

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
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1958770437  85 NGIREAHSQTEKRRRDKMNHLIWKLSSMIPphiPTAHKLDKLSILRRAVQYL 136
Cdd:cd11453     1 STPRSKHSATEQRRRSKINERLQALRDLIP---HSDQKRDKASFLLEVIEYI 49

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
                  ....*....|....*....|....*....|....*....|....*..
gi 1958770437  91 HSQTEKRRRDKMNHLIWKLSSMIPPHIPTAHKLDKLSILRRAVQYLR 137
Cdd:cd11397     9 HNMIERRRRFNINDRIKELGTLLPKSNDPDMRWNKGTILKASVDYIR 55

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        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1958770437  91 HSQTEKRRRDKMNHLIWKLSSMIPPHIP--TAHKLDKLSILRRAVQYLRSQRGMTE 144
Cdd:cd19750    19 HRLIEKKRRDRINECIAQLKDLLPEHLKltTLGHLEKAVVLELTLKHLKALTALTE 74

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
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1958770437  92 SQTEKRRRDKMNHLIWKLSSMIPPHipTAH------KLDKLSILRRAVQYLRSQRGM 142
Cdd:cd11462     6 PLVEKRRRDRINRSLEELRVLLLQN--TQDeklknpKVEKAEILELTVQFLRNSSLS 60

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
                  ....*....|....*....|....*....|....*....|....*
gi 1958770437  95 EKRRRDKMNHLIWKLSSMIPPHIPT--AHKLDKLSILRRAVQYLR 137
Cdd:cd11407     9 EKRRRDRINNSLAELRRLVPTAFEKqgSAKLEKAEILQMTVDHLK 53

basic helix-loop-helix (bHLH) domain found in Arabidopsis thaliana Fe-deficiency induced transcription factor 1 (FIT) and similar proteins; The family includes bHLH transcription factors from Arabidopsis thaliana, such as FIT and DYT1. FIT, also termed FER-like iron deficiency-induced transcription factor, or FER-like regulator of iron uptake, or AtbHLH29, or EN 43, is a bHLH transcription factor that is required for the iron deficiency response in plant. It regulates FRO2 at the level of mRNA accumulation and IRT1 at the level of protein accumulation. DYT1, also termed AtbHLH22, or protein dysfunctional tapetum 1, or EN 49, is a bHLH transcription factor involved in the control of tapetum development. It is required for male fertility and pollen differentiation, especially during callose deposition.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1958770437  94 TEKRRRDKMNHLIWKLSSmippHIPTAHKLDKLSILRRAVQYL 136
Cdd:cd11450    10 SERNRRQKLNQRLFALRS----VVPNITKMDKASIIKDAISYI 48

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in hypoxia-inducible factor 2-alpha (HIF2a) and similar proteins; HIF2a, also termed HIF-2-alpha, or HIF2-alpha, or endothelial PAS domain-containing protein 1 (EPAS-1), or Basic-helix-loop-helix-PAS protein MOP2, or Class E basic helix-loop-helix protein 73 (bHLHe73), or Member of PAS protein 2, or PAS domain-containing protein 2 (PASD2), or HIF-1-alpha-like factor (HLF), is a bHLH-PAS transcription factor involved in the induction of oxygen regulated genes.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1958770437  88 REAHSQTEKR-RRDKMNHLIWKLSSMIP-PHIPTAHkLDKLSILRRAVQYLRSQRGMTEFY 146
Cdd:cd19728     7 RKEKSRDAARcRRSKETEVFYELAHQLPlPHSVSSH-LDKASIMRLAISFLRTHKLLSSVC 66

PAS domain; This domain is found in many signalling proteins in which it functions as a sensor domain. It recognizes FMN, Zn(II), FAD and riboflavin (MAtilla et. al., FEMS Microbiology Reviews, fuab043, 45, 2021, 1. https://doi.org/10.1093/femsre/fuab043).

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1958770437 357 NGKFVYVDQRATAILGYLPQELLGTSCYEYFHQDDHSNLSdkhKAVLQSKEKILTDSYKFRVKDGS 422
Cdd:pfam13426   1 DGRIIYVNDAALRLLGYTREELLGKSITDLFAEPEDSERL---REALREGKAVREFEVVLYRKDGE 63

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 1958770437  87 IREAHSQTEKRRRDKMNHLIWKLSSMIPphiPTAHKLDKLSILRRAVQYL 136
Cdd:cd19683     2 SRERHNAKERQRRERIKIACDQLRKLVP---GCSRKTDKATVFEFTVAYI 48

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in neuronal PAS domain-containing proteins, NPAS1, NPAS3 and similar proteins; The family includes neuronal PAS domain proteins NPAS1 and NPAS3, both of which are master regulators of neuropsychiatric function. NPAS1, also termed neuronal PAS1, or Basic-helix-loop-helix-PAS protein MOP5, or Class E basic helix-loop-helix protein 11 (bHLHe11), or member of PAS protein 5, or PAS domain-containing protein 5 (PASD5), is a bHLH-PAS transcriptional repressor expressed in the central nervous system and involved in neuronal differentiation. It is active during late embryogenesis and postnatal development. NPAS3, also termed neuronal PAS3, or Basic-helix-loop-helix-PAS protein MOP6, or Class E basic helix-loop-helix protein 12 (bHLHe12), or member of PAS protein 6, or PAS domain-containing protein 6 (PASD6), is a bHLH-PAS brain-enriched transcription factor that is involved in central nervous system development and neurogenesis. It is a replicated genetic risk factor for psychiatric disorders. Human chromosomal rearrangements that affect NPAS3 normal expression are associated with schizophrenia and mental retardation.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1958770437  88 REAHSQTEKRRRDKMNHLIWKLSSMIPPHIPTAHKLDKLSILRRAVQYLRSQRGM 142
Cdd:cd11432     1 KEKSRNAARSRRGKENYEFYELAKLLPLPAAISSQLDKASIVRLTISYLKLRDFM 55

RocR-type transcriptional regulator, contains PAS, AAA-type ATPase, and DNA-binding Fis domains [Transcription, Signal transduction mechanisms];

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1958770437 357 NGKFVYVDQRATAILGYLPQELLGTSCYEYFHqddhsnlSDKHKAVLQSKEKILTDSYKFRVKDGSFVT 425
Cdd:COG3829    30 DGRITYVNRAAERILGLPREEVIGKNVTELIP-------NSPLLEVLKTGKPVTGVIQKTGGKGKTVIV 91

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
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1958770437  91 HSQTEKRRRDKMNHLIWKLSSMIPPHIP--TAHKLDKLSILRRAVQYLRSQRGMTE 144
Cdd:cd19749    18 HRLIEKKRRDRINECIAQLKDLLPEHLKltTLGHLEKAVVLELTLKHVKALTSLIE 73