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 966971521  61 QEAHSQTEKRRRDKMNNLIEELSAMIPQCNPMARKLDKLTVLRMAVQHLRSLKGMTNSY 119
Cdd:cd11469    2 REAHSQTEKRRRDKMNNLIEELSAMIPQCNPMARKLDKLTVLRMAVQHLKSLKGSTSSF 60

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 966971521   133 ELRHLILKTAEGFLFVVGcERGKILFVSKSVSKILNYDQASLTGQSLFDFLHPKDVAKVKEQL 195
Cdd:smart00091   1 ERLRAILESLPDGIFVLD-LDGRILYANPAAEELLGYSPEELIGKSLLELIHPEDRERVQEAL 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 966971521  61 QEAHSQTEKRRRDKMNNLIEELSAMIPQCNPMARKLDKLTVLRMAVQHLRSLKGMTNSY 119
Cdd:cd11469    2 REAHSQTEKRRRDKMNNLIEELSAMIPQCNPMARKLDKLTVLRMAVQHLKSLKGSTSSF 60

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 966971521 322 EFITRFAMNGKFVYVDQRATAILGYLPQELLGTSCYEYFHQDDHSNLTDKHKAVLQsKEKILTDSYKFRAKDGSFVTLKS 401
Cdd:cd00130    3 DGVIVLDLDGRILYANPAAEQLLGYSPEELIGKSLLDLIHPEDREELRERLENLLS-GGEPVTLEVRLRRKDGSVIWVLV 81

                         90
                 ....*....|....*....
gi 966971521 402 QWFSFTNPWTKELEYIVSV 420
Cdd:cd00130   82 SLTPIRDEGGEVIGLLGVV 100

helix loop helix domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*...
gi 966971521    68 EKRRRDKMNNLIEELSAMIPQCnPMARKLDKLTVLRMAVQHLRSLKGM 115
Cdd:smart00353   4 ERRRRRKINEAFDELRSLLPTL-PKNKKLSKAEILRLAIEYIKSLQEE 50

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 966971521   133 ELRHLILKTAEGFLFVVGcERGKILFVSKSVSKILNYDQASLTGQSLFDFLHPKDVAKVKEQL 195
Cdd:smart00091   1 ERLRAILESLPDGIFVLD-LDGRILYANPAAEELLGYSPEELIGKSLLELIHPEDRERVQEAL 62

Sporulation sensor histidine kinase E [Cell cycle control, cell division, chromosome partitioning, Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966971521 153 RGKILFVSKSVSKILNYDQASLTGQSLFDFLHPKDVAKVKEQlssfdispreKLIDAKTGLQVHSNFHtgRTHVYsGSRR 232
Cdd:COG5809   34 EGKILKVNPAAERIFGYTEDELLGTNILDFLHPDDEKELREI----------LKLLKEGESRDELEFE--LRHKN-GKRL 100

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966971521 233 SFFCRIKSCKISVKEEHECLPNPKKKEHRKFytihctgylrswppnivgMEEE-RNSKKDNSNFTCLVaigrlqpyiipq 311
Cdd:COG5809  101 EFSSKLSPIFDQNGDIEGMLAISRDITERKR------------------MEEAlRESEEKFRLIFNHS------------ 150

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966971521 312 nsgeihvkpTEFITRFAMNGKFVYVDQRATAILGYLPQELLGTSCYEYFHQDDHSNLTDKHKAVLQSKEkILTDSYKFRA 391
Cdd:COG5809  151 ---------PDGIIVTDLDGRIIYANPAACKLLGISIEELIGKSILELIHSDDQENVAAFISQLLKDGG-IAQGEVRFWT 220

                 ....*...
gi 966971521 392 KDGSFVTL 399
Cdd:COG5809  221 KDGRWRLL 228

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 966971521  133 ELRHLILKTAEGFLFVVGcERGKILFVSKSVSKILNYDQASLTGQSLFDFLHPKDVAKVKEQL 195
Cdd:pfam00989   1 EDLRAILESLPDGIFVVD-EDGRILYVNAAAEELLGLSREEVIGKSLLDLIPEEDDAEVAELL 62

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 966971521  133 ELRHLILKTAEGFLFVVGcERGKILFVSKSVSKILNYDQASLTGQSLFDFLHPKDVAKVKEQLS 196
Cdd:TIGR00229   3 ERYRAIFESSPDAIIVID-LEGNILYVNPAFEEIFGYSAEELIGRNVLELIPEEDREEVRERIE 65

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 966971521  61 QEAHSQTEKRRRDKMNNLIEELSAMIPQCNPMARKLDKLTVLRMAVQHLRSLKGMTNSY 119
Cdd:cd11469    2 REAHSQTEKRRRDKMNNLIEELSAMIPQCNPMARKLDKLTVLRMAVQHLKSLKGSTSSF 60

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 966971521  60 SQEAHSQTEKRRRDKMNNLIEELSAMIPQCNPMARKLDKLTVLRMAVQHLRSLKGMTNSY 119
Cdd:cd19726    1 RRQNHSEIEKRRRDKMNTYITELSSMIPMCNAMSRKLDKLTVLRMAVQHMKTLRGSLTSY 60

PAS domain; This family includes the PAS-B domain of NCOA1 (Nuclear receptor coactivator 1), which binds to an LXXLL motif in the C-terminal region of STAT6 (Signal transducer and activator of transcription 6).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966971521  322 EFITRFAMNGKFVYVDQRATAILGYLPQELLGTSCYEYFHQDDHSNLTDKHKAVLQSKEKILTDSYKFRAKDGSFVTLKS 401
Cdd:pfam14598   3 QFTTRHDIDGKIISCDTRAPFSLGYEKDELVGRSIYDLVHPQDLRTAKSHLREIIQTRGRATSPSYRLRLRDGDFLSVHT 82

                          90       100
                  ....*....|....*....|...
gi 966971521  402 QWFSFTNPWTKELEYIVSVNTLV 424
Cdd:pfam14598  83 KSKLFLNQNSNQQPFIMCTHTIL 105

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 966971521 322 EFITRFAMNGKFVYVDQRATAILGYLPQELLGTSCYEYFHQDDHSNLTDKHKAVLQsKEKILTDSYKFRAKDGSFVTLKS 401
Cdd:cd00130    3 DGVIVLDLDGRILYANPAAEQLLGYSPEELIGKSLLDLIHPEDREELRERLENLLS-GGEPVTLEVRLRRKDGSVIWVLV 81

                         90
                 ....*....|....*....
gi 966971521 402 QWFSFTNPWTKELEYIVSV 420
Cdd:cd00130   82 SLTPIRDEGGEVIGLLGVV 100

Helix-loop-helix DNA-binding domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 966971521   62 EAHSQTEKRRRDKMNNLIEELSAMIPqCNPMARKLDKLTVLRMAVQHLRSLK 113
Cdd:pfam00010   3 EAHNERERRRRDRINDAFDELRELLP-TLPPDKKLSKAEILRLAIEYIKHLQ 53

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 966971521  64 HSQTEKRRRDKMNNLIEELSAMIPQC--NPMARKLDKLTVLRMAVQHLRSLKGMT 116
Cdd:cd11389    1 HKVIEKRRRDRINESLAELRRLVPEArkSKGSGKLEKAEILEMTLQHLKALQSST 55

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 966971521  66 QTEKRRRDKMNNLIEELSAMIPqcnPMARKLDKLTVLRMAVQHLRSLKGMT 116
Cdd:cd11441    6 LSEKKRRDQFNVLINELASMLP---GRGRKMDKSTVLKKTIAFLRKHKELT 53

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 966971521   322 EFITRFAMNGKFVYVDQRATAILGYLPQELLGTSCYEYFHQDDHSNLTDKHKAVLQ 377
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.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 966971521   133 ELRHLILKTAEGFLFVVGcERGKILFVSKSVSKILNYDQASLTGQSLFDFLHPKDVAKVKEQL 195
Cdd:smart00091   1 ERLRAILESLPDGIFVLD-LDGRILYANPAAEELLGYSPEELIGKSLLELIHPEDRERVQEAL 62

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in upstream stimulatory factors, USF1, USF2 and similar proteins; Upstream stimulatory factor 1 and 2 (USF-1 and USF-2) are members of bHLHzip transcription factor family. USFs are ubiquitously expressed and key regulators of a wide number of gene regulation networks, including the stress and immune responses, cell cycle and proliferation, lipid and glucid metabolism. USFs recruit chromatin remodeling enzymes and interact with co-activators and the members of the transcription pre-initiation complex. USFs interact with high affinity to E-box regulatory elements.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 966971521  64 HSQTEKRRRDKMNNLIEELSAMIPQCN--PMARKLDKLTVLRMAVQHLRSLK 113
Cdd:cd11396    2 HNEVERRRRDKINNWIVKLAKIVPDCEkdNSKQGQSKGGILSKACDYIQELR 53

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 966971521  64 HSQTEKRRRDKMNNLIEELSAMIPQCNpmarKLDKLTVLRMAVQHLRSLK 113
Cdd:cd11393    1 HSIAERKRREKINERIRALRSLVPNGG----KTDKASILDEAIEYIKFLQ 46

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 966971521  63 AHSQTEKRRRDKMNNLIEELSAMIPQC--NPMARKLDKLTVLRMAVQHLRSL 112
Cdd:cd11408    1 SHKVIEKRRRDRINRCLNELGKTVPMAlaKQTSGKLEKAEILEMTVQYLRAL 52

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 966971521  67 TEKRRRDKMNNLIEELSAMIPQC----NPMARKLDKLTVLRMAVQHLRSLK 113
Cdd:cd11410    1 MEKKRRARINKSLEQLKTLVLEAlnkdNTRYSKLEKADILEMTVKYLKQLQ 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        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 966971521  56 DSDPSQEA-HSQTEKRRRDKMNNLIEELSAMIPQcnpMARKLDKLTVLRMAVQHLRSLKGMT 116
Cdd:cd19734    2 DKDKAKRVsRNKSEKKRRDQFNVLIKELGSMLPG---NARKMDKSTVLQKSIDFLRKHKEIT 60

basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain found in aryl hydrocarbon receptor (AhR) and similar proteins; 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 dimerize with a bHLH-PAS factor ARNT (Aryl hydrocarbon Nuclear Receptor Translocator).

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 966971521  63 AHSQTEKRRRDKMNNLIEELSAMIPQCNPMARKLDKLTVLRMAVQHLRS 111
Cdd:cd11436    4 VKSNPSKRHRDRLNTELDRLASLLPFPQDVISKLDKLSVLRLSVSYLRA 52

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 966971521  64 HSQTEKRRRDKMNNLIEELSAMIPQCN--PMARKLDKLTVLRMAVQHLRSLK 113
Cdd:cd11387    2 HNAVERRRRDNINEKIQELGSLVPPSRleTKDLKPNKGSILSKAVEYIRELQ 53

basic helix-loop-helix-orange (bHLH-O) domain found in HERP/HES-like family; The HERP/HES-like family includes bHLH-O transcriptional regulators that are related to the Drosophila hairy and Enhancer-of-split (HES) proteins. The HERP (HES-related repressor protein) subfamily proteins contain a basic helix-loop-helix (bHLH) domain with an invariant glycine residue in its basic region, an orange domain in the central region and YXXW sequence motif at its C-terminal region. Hairy and enhancer of split (HES)-related repressor protein (HERP) proteins (HEY1, HEY2 and HEYL) act as downstream effectors of Notch signaling. They are involved in cardiovascular development and have roles in somitogenesis, myogenesis and gliogenesis. Hairy and enhancer of split-related protein HELT is a transcriptional repressor expressed in the developing central nervous system. It binds preferentially to the canonical E box sequence 5'-CACGCG-3' and regulates neuronal differentiation and/or identity. Differentially expressed in chondrocytes proteins, DEC1 and DEC2, are widely expressed in both embryonic and adult tissues and have been implicated in apoptosis, cell proliferation, and circadian rhythms, as well as malignancy in various cancers. Drosophila melanogaster protein clockwork orange (Cwo) is also included in this subfamily. It is involved in the regulation of Drosophila circadian rhythms. It functions as both an activator and a repressor of clock gene expression. The HES subfamily proteins contain a basic helix-loop-helix (bHLH) domain with an invariant proline residue in its basic region, an orange domain in the central region and a conserved tetrapeptide motif, WRPW, at its C-terminal region. They form heterodimers or homodimers via their HLH domain and bind DNA to repress gene transcription that play an essential role in development of both compartment and boundary cells of the central nervous system.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*...
gi 966971521  67 TEKRRRDKMNNLIEELSAMIPQC--NPMARKLDKLTVLRMAVQHLRSL 112
Cdd:cd19685    1 SEKRRRQRINDKLNQLKELLPPNlsKQSRSKLSKAEILEMAITELRRL 48

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 966971521  60 SQEAHSQTEKRRRDKMNNLIEELSAMIPQCNPmarKLDKLTVLRMAVQHLRSLKG 114
Cdd:cd19683    2 SRERHNAKERQRRERIKIACDQLRKLVPGCSR---KTDKATVFEFTVAYIKFLRE 53

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
                 ....*....|....*....|....*....|....*....|....*..
gi 966971521  64 HSQTEKRRRDKMNNLIEELSAMIPQCNPmaRKLDKLTVLRMAVQHLR 110
Cdd:cd18908    6 HSLKERLRRERIKSSCDQLRDLLPYIKG--RKLDMASVLEMTVKYIR 50

PAS domain [Signal transduction mechanisms];

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 966971521 321 TEFITRFAMNGKFVYVDQRATAILGYLPQELLGTSCYEYFHQDDHSNLTDKHKAVLQSKEKILTDSYKFRAKDGSFVTL 399
Cdd:COG2202  147 PDGIFVLDLDGRILYVNPAAEELLGYSPEELLGKSLLDLLHPEDRERLLELLRRLLEGGRESYELELRLKDGDGRWVWV 225

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.

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                 ....*....|....*....|....*....|....*....|....*....|..
gi 966971521  62 EAHSQTEKRRRDKMNNLIEELSAMIPQCNPmaRKLDKLTVLRMAVQHLRSLK 113
Cdd:cd11404    4 LNHVRSEKKRRELIKKGYDELCALVPGLDP--QKRTKADILQKAADWIQELK 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. 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).

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                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 966971521  133 ELRHLILKTAEGFLFVVGcERGKILFVSKSVSKILNYDQASLTGQSLFDFLHPKDVAKVKEQL 195
Cdd:pfam00989   1 EDLRAILESLPDGIFVVD-EDGRILYVNAAAEELLGLSREEVIGKSLLDLIPEEDDAEVAELL 62

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.

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                 ....*....|....*....|....*....|....*....|....*..
gi 966971521  68 EKRRRDKMNNLIEELSAMIPQC--NPMARKLDKLTVLRMAVQHLRSL 112
Cdd:cd11447   17 EKRRRDRINSSLSELRRLVPTAfeKQGSSKLEKAEILQMTVDHLKML 63

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 966971521  61 QEAHSQTEKRRRDKMNNLIEELSAMIPQCNPMARKLDKLTVLRMAVQHLRSLK 113
Cdd:cd18927   12 KDNHNLIERRRRFNINDRIKELGTLIPKTNDLDVRWNKGTILKASVDYIKRMQ 64

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
                 ....*....|....*....|....*....|....*....|....*..
gi 966971521  68 EKRRRDKMNNLIEELSAMIPQC--NPMARKLDKLTVLRMAVQHLRSL 112
Cdd:cd19748   17 EKRRRDRINNSLSELRRLVPSAfeKQGSAKLEKAEILQMTVDHLKML 63

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
                 ....*....|....*....|....*....|....*....|....*....
gi 966971521  68 EKRRRDKMNNLIEELSAMIPQC--NPMARKLDKLTVLRMAVQHLRSLKG 114
Cdd:cd18920   18 EKRRRDRINNSLSELRRLVPTAfeKQGSAKLEKAEILQMTVDHLKMLQA 66

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        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 966971521  59 PSQEAHSQTEKRRRDKMNNLIEELSAMIPQCNPMARKLDKLTVLRMAVQHLRslkgmTNSY 119
Cdd:cd19730    2 KDHPTKSNPSKRHRERLNAELDHLASLLPFEQSVISKLDKLSILRLSVSYLR-----TKSY 57

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 966971521  65 SQTEKRRRDKMNNLIEELSAMIPQC-------NPmarKLDKLTVLRMAVQHLRSLKGM 115
Cdd:cd11462    6 PLVEKRRRDRINRSLEELRVLLLQNtqdeklkNP---KVEKAEILELTVQFLRNSSLS 60

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 966971521  56 DSDPSQEA-HSQTEKRRRDKMNNLIEELSAMIpQCNPMARKLDKLTVLRMAVQHLRSLKGMT 116
Cdd:cd19736    5 EKDRAKRAsRNKSEKKRRDQFNVLIKELCTML-QGHGHPLKMDKSTILQRTIDFLQKQKEIT 65

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 966971521  62 EAHSQTEKRRRDKMNNLIEELSAMIPQCNPmaRKLDKLTVLRMAVQHLRSLKGMTN 117
Cdd:cd18910    7 ESHNEVERRRKDKINAGINKIGELLPDRDA--KKQSKNMILEQAYKYIVELKKKND 60

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]

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 966971521  330 NGKFVYVDQRATAILGYLPQELLGTSCYEYFHQDDHSNLTDKHKAVLQSKEKILTDSYKFRAKDGS 395
Cdd:TIGR00229  22 EGNILYVNPAFEEIFGYSAEELIGRNVLELIPEEDREEVRERIERRLEGEPEPVSEERRVRRKDGS 87

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in Max-binding protein Mnt and similar proteins; Mnt, also termed Class D basic helix-loop-helix protein 3 (bHLHd3), or Myc antagonist MNT, or protein ROX, is a bHLHZip transcriptional repressor that binds DNA as a heterodimer with MAX. It binds to the canonical E box sequence 5'-CACGTG-3' and, with higher affinity, to 5'-CACGCG-3'. Mnt has an important role as an antagonist and regulator of Myc activities and it is a potential tumor suppressor. Mnt is ubiquitously expressed. Mnt-deficient mice shown to exhibit early postnatal lethality.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 966971521  60 SQEAHSQTEKRRRDKMNNLIEELSAMIPQCNPmaRKLDKLTVLRMAVQHLRSLKGMTNSYV 120
Cdd:cd11402    2 TREVHNKLEKNRRAHLKECFETLKRQIPNLDD--KKTSNLNILRSALRYIQILKRKEKEYE 60