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        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 30795242  71 KERFARENHSEIERRRRNKMTAYITELSDMVPTCSALARKPDKLTILRMAVSHMKSLRGTGNTST 135
Cdd:cd18947   1 KERFARENHSEIERRRRNKMTAYITELSDMVPTCSALARKPDKLTILRMAVSHMKSLRGTGNTST 65

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 30795242   148 ELKHLILEAADGFLFIVScETGRVVYVSDSVTPVLNQPQSEWFGSTLYDQVHPDD----VDKLREQLSTSENALTGRI-L 222
Cdd:pfam00989   1 EDLRAILESLPDGIFVVD-EDGRILYVNAAAEELLGLSREEVIGKSLLDLIPEEDdaevAELLRQALLQGEESRGFEVsF 79

                          90       100       110
                  ....*....|....*....|....*....|...
gi 30795242   223 DLKTGTVKKEGQQSSMRMCMGSR-RSFICRMRC 254
Cdd:pfam00989  80 RVPDGRPRHVEVRASPVRDAGGEiLGFLGVLRD 112

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        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 30795242  71 KERFARENHSEIERRRRNKMTAYITELSDMVPTCSALARKPDKLTILRMAVSHMKSLRGTGNTST 135
Cdd:cd18947   1 KERFARENHSEIERRRRNKMTAYITELSDMVPTCSALARKPDKLTILRMAVSHMKSLRGTGNTST 65

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 30795242 347 EFISRHNIEGIFTFVDHRCVATVGYQPQELLGKNIVEFCHPEDQQLLRDSFQQVVKlKGQVLSVMFRFRSKNQEWLWMRT 426
Cdd:cd00130   3 DGVIVLDLDGRILYANPAAEQLLGYSPEELIGKSLLDLIHPEDREELRERLENLLS-GGEPVTLEVRLRRKDGSVIWVLV 81

                        90
                ....*....|....*..
gi 30795242 427 SSFTFQNPYSDEIEYII 443
Cdd:cd00130  82 SLTPIRDEGGEVIGLLG 98

helix loop helix domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 30795242     80 SEIERRRRNKMTAYITELSDMVPTCSAlARKPDKLTILRMAVSHMKSLR 128
Cdd:smart00353   1 NARERRRRRKINEAFDELRSLLPTLPK-NKKLSKAEILRLAIEYIKSLQ 48

PAS domain [Signal transduction mechanisms];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30795242 346 TEFISRHNIEGIFTFVDHRCVATVGYQPQELLGKNIVEFCHPEDQQLLRDSFQQVVKLKGQVLSVMFRFRSKNQEWLWMR 425
Cdd:COG2202 147 PDGIFVLDLDGRILYVNPAAEELLGYSPEELLGKSLLDLLHPEDRERLLELLRRLLEGGRESYELELRLKDGDGRWVWVE 226

                        90       100
                ....*....|....*....|....
gi 30795242 426 TSSFTFQNpySDEIEYIICTNTNV 449
Cdd:COG2202 227 ASAVPLRD--GGEVIGVLGIVRDI 248

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        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 30795242    151 HLILEAADGFLFIVScETGRVVYVSDSVTPVLNQPQSEWFGSTLYDQVHPDDVDKLREQLSTSEN 215
Cdd:smart00091   4 RAILESLPDGIFVLD-LDGRILYANPAAEELLGYSPEELIGKSLLELIHPEDRERVQEALQRLLS 67

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        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 30795242   355 EGIFTFVDHRCVATVGYQPQELLGKNIVEFCHPEDQQLLRDSFQQVVKLKGQVLSVMFRFRSKNQEWLWMRTS 427
Cdd:TIGR00229  22 EGNILYVNPAFEEIFGYSAEELIGRNVLELIPEEDREEVRERIERRLEGEPEPVSEERRVRRKDGSEIWVEVS 94

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        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 30795242  71 KERFARENHSEIERRRRNKMTAYITELSDMVPTCSALARKPDKLTILRMAVSHMKSLRGTGNTST 135
Cdd:cd18947   1 KERFARENHSEIERRRRNKMTAYITELSDMVPTCSALARKPDKLTILRMAVSHMKSLRGTGNTST 65

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        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 30795242  76 RENHSEIERRRRNKMTAYITELSDMVPTCSALARKPDKLTILRMAVSHMKSLRGTGNTSTD 136
Cdd:cd19726   2 RQNHSEIEKRRRDKMNTYITELSSMIPMCNAMSRKLDKLTVLRMAVQHMKTLRGSLTSYTE 62

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
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 30795242  76 RENHSEIERRRRNKMTAYITELSDMVPTCSALARKPDKLTILRMAVSHMKSLRGTGNT 133
Cdd:cd11469   2 REAHSQTEKRRRDKMNNLIEELSAMIPQCNPMARKLDKLTVLRMAVQHLKSLKGSTSS 59

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 30795242   358 FTFVDHRCVATVGYQPQELLGK--NIVEFCHPEDQQLLRDSFQQVVKlKGQVLSVMFRFRSKNQEWLWMRTSSFTFQNPy 435
Cdd:pfam08447   1 IIYWSPRFEEILGYTPEELLGKgeSWLDLVHPDDRERVREALWEALK-GGEPYSGEYRIRRKDGEYRWVEARARPIRDE- 78

                          90
                  ....*....|.
gi 30795242   436 SDEIEYIICTN 446
Cdd:pfam08447  79 NGKPVRVIGVA 89

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 30795242 347 EFISRHNIEGIFTFVDHRCVATVGYQPQELLGKNIVEFCHPEDQQLLRDSFQQVVKlKGQVLSVMFRFRSKNQEWLWMRT 426
Cdd:cd00130   3 DGVIVLDLDGRILYANPAAEQLLGYSPEELIGKSLLDLIHPEDREELRERLENLLS-GGEPVTLEVRLRRKDGSVIWVLV 81

                        90
                ....*....|....*..
gi 30795242 427 SSFTFQNPYSDEIEYII 443
Cdd:cd00130  82 SLTPIRDEGGEVIGLLG 98

helix loop helix domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 30795242     80 SEIERRRRNKMTAYITELSDMVPTCSAlARKPDKLTILRMAVSHMKSLR 128
Cdd:smart00353   1 NARERRRRRKINEAFDELRSLLPTLPK-NKKLSKAEILRLAIEYIKSLQ 48

PAS domain [Signal transduction mechanisms];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 30795242 346 TEFISRHNIEGIFTFVDHRCVATVGYQPQELLGKNIVEFCHPEDQQLLRDSFQQVVKLKGQVLSVMFRFRSKNQEWLWMR 425
Cdd:COG2202 147 PDGIFVLDLDGRILYVNPAAEELLGYSPEELLGKSLLDLLHPEDRERLLELLRRLLEGGRESYELELRLKDGDGRWVWVE 226

                        90       100
                ....*....|....*....|....
gi 30795242 426 TSSFTFQNpySDEIEYIICTNTNV 449
Cdd:COG2202 227 ASAVPLRD--GGEVIGVLGIVRDI 248

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 30795242  79 HSEIERRRRNKMTAYITELSDMVPTCSALAR--KPDKLTILRMAVSHMKSLRGTG 131
Cdd:cd11389   1 HKVIEKRRRDRINESLAELRRLVPEARKSKGsgKLEKAEILEMTLQHLKALQSST 55

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        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 30795242    151 HLILEAADGFLFIVScETGRVVYVSDSVTPVLNQPQSEWFGSTLYDQVHPDDVDKLREQLSTSEN 215
Cdd:smart00091   4 RAILESLPDGIFVLD-LDGRILYANPAAEELLGYSPEELIGKSLLELIHPEDRERVQEALQRLLS 67

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

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 30795242  70 DKERFARENHSEIERRRRNKMTAYITELSDMVPtcsALARKPDKLTILRMAVSHMKSL 127
Cdd:cd11398   2 EWHRQRRDNHKEVERRRRENINEGINELAALVP---GNAREKNKGAILARAVEYIQEL 56

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 30795242  70 DKERfaRENHSEIERRRRNKMTAYITELSDMVPTCSALARKP--DKLTILRMAVSHMKSLR 128
Cdd:cd18924   2 DEKR--RAQHNEVERRRRDKINNWIVQLSKIIPDCSMESTKSgqSKGGILSKACDYIQELR 60

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        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 30795242  78 NHSEIERRRRNKMTAYITELSDMVPTC--SALARKPDKLTILRMAVSHMKSLR 128
Cdd:cd11387   1 SHNAVERRRRDNINEKIQELGSLVPPSrlETKDLKPNKGSILSKAVEYIRELQ 53

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

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 30795242  70 DKERfaRENHSEIERRRRNKMTAYITELSDMVPTCSALARK--PDKLTILRMAVSHMKSLRGTgNTSTDGSYK 140
Cdd:cd18923   5 DERR--RAQHNEVERRRRDKINNWIVQLSKIIPDCNTDNSKtgASKGGILSKACDYIRELRQT-NQRMQETYK 74

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

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 30795242  73 RFARENHSEIERRRRNKMTAYITELSDMVPTCS--------------ALARKPDKLTILRMAVSHMKSL 127
Cdd:cd11395   1 PRKRLPHNAIEKRYRSNLNTKIERLRDAIPSLRspegksddgglgglAPTTKLSKATILTKAIEYIRHL 69

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        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 30795242   355 EGIFTFVDHRCVATVGYQPQELLGKNIVEFCHPEDQQLLRDSFQQVVKLKGQVLSVMFRFRSKNQEWLWMRTS 427
Cdd:TIGR00229  22 EGNILYVNPAFEEIFGYSAEELIGRNVLELIPEEDREEVRERIERRLEGEPEPVSEERRVRRKDGSEIWVEVS 94

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 30795242  75 ARENHSEI-ERRRRNKMTAYITELSDMVPTC--SALARKPDKLTILRMAVSHMKSLRGTGNT 133
Cdd:cd11447   8 ARKKRRGIiEKRRRDRINSSLSELRRLVPTAfeKQGSSKLEKAEILQMTVDHLKMLHATGGA 69

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 30795242  79 HSEIERRRRNKMTAYITELSDMVPTCsalaRKPDKLTILRMAVSHMKSLR 128
Cdd:cd11393   1 HSIAERKRREKINERIRALRSLVPNG----GKTDKASILDEAIEYIKFLQ 46

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 30795242   353 NIEGIFTFVDHRCVATVGYQPQELLGKNIVEFCHPEDQQLLRDSFQQVVKLKGQVLSVMFRFRSKNQEWLWMRTSSFTFQ 432
Cdd:pfam00989  18 DEDGRILYVNAAAEELLGLSREEVIGKSLLDLIPEEDDAEVAELLRQALLQGEESRGFEVSFRVPDGRPRHVEVRASPVR 97

                          90
                  ....*....|...
gi 30795242   433 NPySDEIEYIICT 445
Cdd:pfam00989  98 DA-GGEILGFLGV 109

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 30795242  75 ARENHSEIERRRRNKMTAYITELSDMVPTCSalarKPDKLTILRMAVSHMKSL 127
Cdd:cd11445   2 AAEVHNLSERRRRDRINEKMKALQELIPNCN----KTDKASMLDEAIEYLKSL 50

basic helix-loop-helix-orange (bHLH-O) domain found in Drosophila melanogaster enhancer of split mbeta protein (ESMB) and similar proteins; ESMB, also termed E(spl)mbeta, or HLH-mbeta, or split locus enhancer protein mA, is a bHLH-O transcriptional repressor of genes that require a bHLH protein for their transcription. It is involved in the neural-epidermal lineage decision during early neurogenesis. The family also includes Enhancer of split m7 protein (also known as E(spl)m7), which acts as a transcriptional repressor that participates in the control of cell fate choice by uncommitted neuroectodermal cells in the embryo.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 30795242  82 IERRRRNKMTAYITELSDMVPTCSALARKPD----KLTILRMAVSHMKSLR 128
Cdd:cd19741  15 LERKRRARINKCLDELKDLMVEALATEAENVskleKADILELTVRHLKKLR 65

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 30795242  78 NHSEIERRRRNKMTAYITELSDMVPtcSALAR----KPDKLTILRMAVSHMKSLRGTG 131
Cdd:cd11408   1 SHKVIEKRRRDRINRCLNELGKTVP--MALAKqtsgKLEKAEILEMTVQYLRALHSAD 56

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in Max-like protein X (Mlx) family; Mlx, also termed Class D basic helix-loop-helix protein 13 (bHLHd13), or Max-like bHLHZip protein, or protein BigMax, or transcription factor-like protein 4, is a Max-like bHLHZip transcription regulator that interacts with the Max network of transcription factors. It forms a sequence-specific DNA-binding protein complex with some member of Mad family (Mad1 and Mad4) and Mondo family but not the Myc family and bind the E-box DNA to control transcription. The family also includes Saccharomyces cerevisiae INO4, which 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 30795242  76 RENHSEIERRRRNKMTAYITELSDMVPTCSalARKPDKLTILRMAVSHMKSL 127
Cdd:cd11404   3 RLNHVRSEKKRRELIKKGYDELCALVPGLD--PQKRTKADILQKAADWIQEL 52

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 30795242  82 IERRRRNKMTAYITELSDMVPTCSAL--ARKPDKLTILRMAVSHMKSLR 128
Cdd:cd19685   1 SEKRRRQRINDKLNQLKELLPPNLSKqsRSKLSKAEILEMAITELRRLQ 49

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        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 30795242  70 DKERFARENHSEIERRRRNKMTAYITELSDMVPTCSalarKPDKLTILRMAVSHMKSLRGT 130
Cdd:cd11455   2 DKALAASKSHSEAERRRRERINSHLATLRTLLPNLS----KTDKASLLAEVVQHVKELKRQ 58

basic helix-loop-helix-orange (bHLH-O) domain found in hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1) and similar proteins; HEY1, also termed cardiovascular helix-loop-helix factor 2 (CHF-2), or Class B basic helix-loop-helix protein 31 (bHLHb31), or HES-related repressor protein 1, or hairy and enhancer of split-related protein 1 (HESR-1), or hairy-related transcription factor 1 (HRT-1), is a bHLH-O transcriptional repressor that acts as an essential downstream effector of the Notch signaling pathway and may play a fundamental role in vascular development. HEY1 also participates several cancer-related pathways. It acts as a positive regulator of the tumor suppressor p53.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 30795242  63 DDDQMSNDKERfarenHSEIERRRRNKMTAYITELSDMVPTC-----SAlarKPDKLTILRMAVSHMKSLRGTG 131
Cdd:cd19748   2 TSSQVLARKRR-----RGIIEKRRRDRINNSLSELRRLVPSAfekqgSA---KLEKAEILQMTVDHLKMLHAAG 67

Motif C-terminal to PAS motifs (likely to contribute to PAS structural domain); PAC motif occurs C-terminal to a subset of all known PAS motifs. It is proposed to contribute to the PAS domain fold.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|.
gi 30795242    409 SVMFRFRSKNQEWLWMRTSSFTFQNpYSDEIEYIICTNTNV 449
Cdd:smart00086   1 TVEYRLRRKDGSYIWVLVSASPIRD-EDGEVEGILGVVRDI 40

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        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 30795242  76 RENHSEIERRRRNKMTAYITELSDMVPTCSAlarKPDKLTILRMAVSHMKSLRG 129
Cdd:cd18909   3 RERHNRMERDRRRRIRICCDELNLLVPFCNA---ETDKATTLQWTTAFLKYIQE 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
                ....*....|....*....|....*....|....*....|....*....|....*
gi 30795242  76 RENHSEIERRRRNKMTAYITELSDMVPtcsALARKPD--KLTILRMAVSHMKSLR 128
Cdd:cd11400   2 RRLHNVLERQRRNDLKNSFEKLRDLVP---ELADNEKasKVVILKKATEYIKQLQ 53

basic helix-loop-helix-orange (bHLH-O) domain found in hairy and enhancer of split (HES) family; The HES family includes bHLH-O transcriptional regulators that are related to the Drosophila hairy and Enhancer-of-split (HES) proteins. They 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. HES family proteins 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 30795242  82 IERRRRNKMTAYITELSDMVPTCSAL----ARKPDKLTILRMAVSHMKSLR 128
Cdd:cd11410   1 MEKKRRARINKSLEQLKTLVLEALNKdntrYSKLEKADILEMTVKYLKQLQ 51

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in N-Myc and similar proteins; N-Myc, also termed Class E basic helix-loop-helix protein 37 (bHLHe37), is a bHLHZip proto-oncogene protein that positively regulates the transcription of MYCNOS in neuroblastoma cells. It is also essential during embryonic development. N-Myc has a critical role in regulating the switch between proliferation and differentiation of progenitor cells. It binds DNA as a heterodimer with MAX. The family also includes S-Myc, encoded by rat or mouse intronless myc gene, which has apoptosis-inducing activity.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 30795242  70 DKERfaRENHSEIERRRRNKMTAYITELSDMVPTCsALARKPDKLTILRMAVSHMKSLR 128
Cdd:cd11456   2 DSER--RRNHNILERQRRNDLRSSFLTLRDHVPEL-VKNEKAAKVVILKKATEYVHSLQ 57

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in single-minded (SIM) family; The SIM family includes Drosophila melanogaster protein SIM and its homologs from vertebrates, single-minded homolog 1 (SIM1) and single-minded homolog 2 (SIM2). 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. 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. SIM2, also termed Class E basic helix-loop-helix protein 15 (bHLHe15), is a bHLH-PAS transcription factor that may be a master gene of central nervous system (CNS) development in cooperation with ARNT. It may have pleiotropic effects in the tissues expressed during development.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 30795242  76 RENHSEIERRRRNKMTAYITELSDMVPTCSALARKPDKLTILRMAVSHMK 125
Cdd:cd11434   2 KEKSKNAARTRREKENAEFYELAKLLPLPSAITSQLDKASIIRLTTSYLK 51

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

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 30795242  79 HSEIERRRRNKMTAYITELSDMVPTCSalaRKPDKLTILRMAVSHMKSLR 128
Cdd:cd19698   1 HNLLEKKRRERIKDKIEILKGLTPNCT---PKSDIASILSCVIDYIKSLL 47

basic helix-loop-helix (bHLH) domain found in Arabidopsis thaliana protein ABA-INDUCIBLE bHLH-TYPE (AIB) and similar proteins; The family includes several bHLH transcription factors from Arabidopsis thaliana, such as AIB and MYC proteins (MYC2, MYC3 and MYC4). AIB, also termed AtbHLH17, or EN 35, is a transcription activator that regulates positively abscisic acid (ABA) response. MYC2, also termed protein jasmonate insensitive 1, or R-homologous Arabidopsis protein 1 (RAP-1), or AtbHLH6, or EN 38, or Z-box binding factor 1 protein, is a transcriptional activator involved in abscisic acid (ABA), jasmonic acid (JA), and light signaling pathways. MYC3, also termed protein altered tryptophan regulation 2, or AtbHLH5, or transcription factor ATR2, or EN 36, is a transcription factor involved in tryptophan, jasmonic acid (JA) and other stress-responsive gene regulation. MYC4, also termed AtbHLH4, or EN 37, is a transcription factor involved in jasmonic acid (JA) gene regulation. MYC2, together with MYC3 and MYC4, controls additively subsets of JA-dependent responses.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 30795242  78 NHSEIERRRRNKMTAYITELSDMVPTCSalarKPDKLTILRMAVSHMKSLR 128
Cdd:cd11449   8 NHVEAERQRREKLNQRFYALRAVVPNVS----KMDKASLLGDAISYINELK 54

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

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 30795242  76 RENHSEIERRRRNKMTAYITELSDMVPTCSALARKPdKLTILRMAVSHMKSL 127
Cdd:cd11457   8 RKNHNFLERKRRNDLRSRFLALRDEVPGLASCSKTP-KVVILSKATEYLRGL 58

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in hypoxia-inducible factor (HIF) family; The HIF family contains bHLH-PAS transcription regulators involved in oxygen homeostasis, including HIF1a, HIF2a, and HIF3a. They have been implicated in development, postnatal physiology as well as disease pathogenesis. HIF1a, also termed HIF-1-alpha, or HIF1-alpha, or ARNT-interacting protein, or Basic-helix-loop-helix-PAS protein MOP1, or Class E basic helix-loop-helix protein 78 (bHLHe78), or Member of PAS protein 1, or PAS domain-containing protein 8 (PASD8), functions as a master transcriptional regulator of the adaptive response to hypoxia. 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. HIF3a, also termed HIF-3-alpha, or HIF3-alpha, or endothelial PAS domain-containing protein 1 (EPAS-1), or Basic-helix-loop-helix-PAS protein MOP7, or Class E basic helix-loop-helix protein 17 (bHLHe17), or Member of PAS protein 7, or PAS domain-containing protein 7 (PASD7), or HIF3-alpha-1, or inhibitory PAS domain protein (IPAS), is a bHLH-PAS transcriptional regulator in adaptive response to low oxygen tension. It plays a role in the regulation of hypoxia-inducible gene expression.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|..
gi 30795242  84 RRRRNKMTAYITELSDMVPTCSALARKPDKLTILRMAVSHMK 125
Cdd:cd11433  10 RCRRGKESEIFYELAHQLPLPHSVSSQLDKASIMRLTISYLK 51

basic helix-loop-helix (bHLH) domain found in the spermatogenesis- and oogenesis-specific basic helix-loop-helix-containing protein (SOHLH) family; 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 30795242  79 HSEIERRRRNKMTAYITELSDMVPTCSalARKPDKLTILRMAVSHMKSLR 128
Cdd:cd18908   6 HSLKERLRRERIKSSCDQLRDLLPYIK--GRKLDMASVLEMTVKYIRYIQ 53

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 30795242  69 NDKERFARENHSEIERRRRNKMTAYITELSDMVPTCSalaRKPDKLTILRMAVSHMK 125
Cdd:cd19737   4 DEKDRAKRASRNKSEKKRRDQFNVLIKELSSMLPGNT---RKMDKTTVLEKVIGFLQ 57