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 665390794  38 REARNLAEKQRRDKLNASIQELATMVPHAAESSRRLDKTAVLRFATHGLRLQ 89
Cdd:cd11391    1 REKSREAAKKRRDKENAEISELASLLPLPPAVGSKLDKLSVLRLAVAYLRLK 52

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 665390794  38 REARNLAEKQRRDKLNASIQELATMVPHAAESSRRLDKTAVLRFATHGLRLQ 89
Cdd:cd11391    1 REKSREAAKKRRDKENAEISELASLLPLPPAVGSKLDKLSVLRLAVAYLRLK 52

helix loop helix domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 665390794    42 NLAEKQRRDKLNASIQELATMVPhAAESSRRLDKTAVLRFAT 83
Cdd:smart00353   1 NARERRRRRKINEAFDELRSLLP-TLPKNKKLSKAEILRLAI 41

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
                   ....*....|....*....|....*....|....*....|....
gi 665390794   144 GQIVLVSTSVEQLLGHCQSDLYGQNLLQITHPDDQDLLRQQLIP 187
Cdd:smart00091  21 GRILYANPAAEELLGYSPEELIGKSLLELIHPEDRERVQEALQR 64

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 665390794  38 REARNLAEKQRRDKLNASIQELATMVPHAAESSRRLDKTAVLRFATHGLRLQ 89
Cdd:cd11391    1 REKSREAAKKRRDKENAEISELASLLPLPPAVGSKLDKLSVLRLAVAYLRLK 52

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL) and similar proteins; 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.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 665390794  36 NGREARNLAEKQRRDKLNASIQELATMVPHAAESSRRLDKTAVLRFATHGLR 87
Cdd:cd11438    6 NAREAHSQIEKRRRDKMNSFIDELASLVPTCNAMSRKLDKLTVLRMAVQHMK 57

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 665390794  38 REARNLAEKQRRDKLNASIQELATMVPhaaESSRRLDKTAVLRFATHGLRLQ 89
Cdd:cd11441    1 RKSRNLSEKKRRDQFNVLINELASMLP---GRGRKMDKSTVLKKTIAFLRKH 49

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in Drosophila melanogaster protein cycle and similar proteins; 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
                 ....*....|....*....|....*....|....*....|...
gi 665390794  45 EKQRRDKLNASIQELATMVPHAAESSRRLDKTAVLRFATHGLR 87
Cdd:cd19726    9 EKRRRDKMNTYITELSSMIPMCNAMSRKLDKLTVLRMAVQHMK 51

helix loop helix domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 665390794    42 NLAEKQRRDKLNASIQELATMVPhAAESSRRLDKTAVLRFAT 83
Cdd:smart00353   1 NARERRRRRKINEAFDELRSLLP-TLPKNKKLSKAEILRLAI 41

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in Drosophila melanogaster protein single-minded (SIM) and similar proteins; SIM is a nuclear bHLH-PAS transcription factor that functions as a master developmental regulator controlling midline development of the ventral nerve cord in Drosophila.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 665390794  38 REARNLAEKQRRDKLNASIQELATMVPHAAESSRRLDKTAVLRFATHGLRLQYVF 92
Cdd:cd19740    2 KEKSKNAARSRREKENAEFLELAKLLPLPAAITSQLDKASIIRLTTSYLKMRQVF 56

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 665390794  38 REARNLAEKQRRDKLNASIQELATMVPHaaeSSRRLDKTAVLRFATHGLR 87
Cdd:cd19734    8 RVSRNKSEKKRRDQFNVLIKELGSMLPG---NARKMDKSTVLQKSIDFLR 54

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in aryl hydrocarbon receptor nuclear translocator (ARNT) and similar proteins; ARNT, also termed Class E basic helix-loop-helix protein 2 (bHLHe2), or Dioxin receptor, nuclear translocator, or hypoxia-inducible factor 1-beta (HIF1b), or HIF-1-beta, or HIF1-beta, is a member of bHLH-PAS transcription regulators that acts 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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*
gi 665390794  38 REARNLAEKQRRDKLNASIQELATMVPHAAESSRRLDKTAVLRFA 82
Cdd:cd18947    6 RENHSEIERRRRNKMTAYITELSDMVPTCSALARKPDKLTILRMA 50

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
                 ....*....|....*....|....*....|....*.
gi 665390794  45 EKQRRDKLNASIQELATMVPhAAESSRRLDKTAVLR 80
Cdd:cd00083    1 ERRRRDKINDAFEELKRLLP-ELPDSKKLSKASILQ 35

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
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 665390794  38 REARNLAEKQRRDKLNASIQELATMVPHAAES--SRRLDKTAVLRFATHGLRLQYVFG 93
Cdd:cd11447   10 KKRRGIIEKRRRDRINSSLSELRRLVPTAFEKqgSSKLEKAEILQMTVDHLKMLHATG 67

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
                 ....*....|....*....|....*....|....*....|....*....|...
gi 665390794  38 REARNLAEKQRRDKLNASIQELATMVPHAAE--SSRRLDKTAVLRFATHGLRL 88
Cdd:cd11407    2 KKRRGIIEKRRRDRINNSLAELRRLVPTAFEkqGSAKLEKAEILQMTVDHLKM 54

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in single-minded homolog 1 (SIM1) and similar proteins; SIM1, also termed Class E basic helix-loop-helix protein 14 (bHLHe14), is a bHLH-PAS transcription factor that may have pleiotropic effects during embryogenesis and in the adult.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 665390794  38 REARNLAEKQRRDKLNASIQELATMVPHAAESSRRLDKTAVLRFATHGLRLQYVF 92
Cdd:cd19738    2 KEKSKNAARTRREKENSEFYELAKLLPLPSAITSQLDKASIIRLTTSYLKMRVVF 56

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 665390794  46 KQRRDKLNASIQELATMVPHAAESSRRLDKTAVLRFATHGLRLQYVFG 93
Cdd:cd19696    9 KRHRDRLNSELDELASLLPFPEDVISKLDKLSVLRLSVSYLRTKNYFQ 56

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
                 ....*....|....*....|....*....|....*....|....*
gi 665390794  45 EKQRRDKLNASIQELATMVPHA--AESSRRLDKTAVLRFATHGLR 87
Cdd:cd11408    6 EKRRRDRINRCLNELGKTVPMAlaKQTSGKLEKAEILEMTVQYLR 50

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
                  ....*....|....*....|....*....|....*....|...
gi 665390794  143 SGQIVLVSTSVEQLLGHCQSDLYGQNLLQITHPDDQDLLRQQL 185
Cdd:TIGR00229  22 EGNILYVNPAFEEIFGYSAEELIGRNVLELIPEEDREEVRERI 64

basic helix-loop-helix-orange (bHLH-O) domain found in hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2) and similar proteins; HEY2, also termed cardiovascular helix-loop-helix factor 1 (CHF-1), or Class B basic helix-loop-helix protein 32 (bHLHb32), or HES-related repressor protein 2, or hairy and enhancer of split-related protein 2 (HESR-2), or hairy-related transcription factor 2 (HRT-2), or protein gridlock homolog, is a bHLH-O transcriptional repressor expressed preferentially in the developing and adult cardiovascular system. As a downstream effector of Notch signaling, HEY2 may be required for cardiovascular development. It also plays an important role in neurologic development, as well as in the progression of human cancers.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 665390794  38 REARNLAEKQRRDKLNASIQELATMVPHAAES--SRRLDKTAVLRFATHGLR-LQYVFGK 94
Cdd:cd18920   11 KKRRGIIEKRRRDRINNSLSELRRLVPTAFEKqgSAKLEKAEILQMTVDHLKmLQATGGK 70

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
                 ....*....|....*....|...
gi 665390794  42 NLAEKQRRDKLNASIQELATMVP 64
Cdd:cd11387    3 NAVERRRRDNINEKIQELGSLVP 25

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

                         10        20
                 ....*....|....*....|....*..
gi 665390794  38 REARNLAEKQRRDKLNASIQELATMVP 64
Cdd:cd11392    3 RTAHKVAERGRRDRLNAALKELASLMP 29