basic Helix Loop Helix (bHLH) domain superfamily; bHLH proteins are transcriptional regulators that are found in organisms from yeast to humans. Members of the bHLH superfamily have two highly conserved and functionally distinct regions. The basic part is at the amino end of the bHLH that may bind DNA to a consensus hexanucleotide sequence known as the E box (CANNTG). Different families of bHLH proteins recognize different E-box consensus sequences. At the carboxyl-terminal end of the region is the HLH region that interacts with other proteins to form homo- and heterodimers. bHLH proteins function as a diverse set of regulatory factors because they recognize different DNA sequences and dimerize with different proteins. The bHLH proteins can be divided to cell-type specific and widely expressed proteins. The cell-type specific members of bHLH superfamily are involved in cell-fate determination and act in neurogenesis, cardiogenesis, myogenesis, and hematopoiesis.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1907069810  24 GDRKARKPLVEKKRRARINESLQELRLLLAGTEVQAKLENAEVLELTVRRVQGALRGR 81
Cdd:cd11460     1 GDRKARKPLVEKKRRARINESLQELRLILADAELQSKMENAEVLELTVKRVQGILRNR 58

basic helix-loop-helix-orange (bHLH-O) domain found in transcription factor HES-6 and similar proteins; HES-6, also termed Class B basic helix-loop-helix protein 41 (bHLHb41), or hairy and enhancer of split 6, or C-HAIRY1, is a bHLH-O transcription factor that is expressed in developing muscle and involved in angiogenesis, myogenesis, neural differentiation and neurogenesis. HES-6 antagonizes Notch signaling but is not regulated by Notch signaling. It is a transcription co-factor associated with stem cell characteristics in neural tissue. It may act as an inhibitor of Hes-1 during neuronal development and forms a heterodimer with HES-1 to prevent its association with transcriptional co-repressors. The overexpression of HES-6 has been reported in metastatic cancers of different origins. HES-6 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 1907069810  24 GDRKARKPLVEKKRRARINESLQELRLLLAGTEVQAKLENAEVLELTVRRVQGALRGR 81
Cdd:cd11460     1 GDRKARKPLVEKKRRARINESLQELRLILADAELQSKMENAEVLELTVKRVQGILRNR 58

Hairy Orange; The Orange domain is found in the Drosophila proteins Hesr-1, Hairy, and Enhancer of Split. The Orange domain is proposed to mediate specific protein-protein interaction between Hairy and Scute.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1907069810  95 RFAAGYIQCMHEVHTFVSTCQAIDATVSAELLNHLLESMP 134
Cdd:pfam07527   1 RFRAGFNECANEVSRFLSTLEGVDPDLRQRLLNHLQRCLA 40

Orange domain; This domain confers specificity among members of the Hairy/E(SPL) family.

                           10        20        30
                   ....*....|....*....|....*....|....
gi 1907069810   96 FAAGYIQCMHEVHTFVSTCQAIDATVSAELLNHL 129
Cdd:smart00511   3 FRSGYRECANEVSRFLSQLPGTDPDVRARLLSHL 36

basic helix-loop-helix-orange (bHLH-O) domain found in transcription factor HES-6 and similar proteins; HES-6, also termed Class B basic helix-loop-helix protein 41 (bHLHb41), or hairy and enhancer of split 6, or C-HAIRY1, is a bHLH-O transcription factor that is expressed in developing muscle and involved in angiogenesis, myogenesis, neural differentiation and neurogenesis. HES-6 antagonizes Notch signaling but is not regulated by Notch signaling. It is a transcription co-factor associated with stem cell characteristics in neural tissue. It may act as an inhibitor of Hes-1 during neuronal development and forms a heterodimer with HES-1 to prevent its association with transcriptional co-repressors. The overexpression of HES-6 has been reported in metastatic cancers of different origins. HES-6 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 1907069810  24 GDRKARKPLVEKKRRARINESLQELRLLLAGTEVQAKLENAEVLELTVRRVQGALRGR 81
Cdd:cd11460     1 GDRKARKPLVEKKRRARINESLQELRLILADAELQSKMENAEVLELTVKRVQGILRNR 58

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
                  ....*....|....*....|....*....|....*....|....*...
gi 1907069810  33 VEKKRRARINESLQELRLLLAG-----TEVQAKLENAEVLELTVRRVQ 75
Cdd:cd11410     1 MEKKRRARINKSLEQLKTLVLEalnkdNTRYSKLEKADILEMTVKYLK 48

basic helix-loop-helix-orange (bHLH-O) domain found in transcription factor HES-5 and similar proteins; HES-5, also termed Class B basic helix-loop-helix protein 38 (bHLHb38), or hairy and enhancer of split 5, is a bHLH-O transcription factor that is involved in cell differentiation and proliferation in a variety of tissues. HES-5 is an essential effector for Notch signaling. It acts as a transducer of Notch signals in brain vascular development. It also acts as a key mediator of Wnt-3a-induced neuronal differentiation and plays a crucial role in normal inner ear hair cell development. HES-5 is one mammalian counterpart of the Hairy and Enhancer of split proteins that play a critical role in many physiological processes including cellular differentiation, cell cycle arrest, apoptosis and self-renewal ability.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1907069810  27 KARKPLVEKKRRARINESLQELRLLLaGTEVQ-----AKLENAEVLELTV 71
Cdd:cd11461     1 KLRKPVVEKTRRDRINSSIEQLKTLL-EKEFQrhqpnSKLEKADILEMTV 49

Helix-loop-helix DNA-binding domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1907069810  26 RKARKPLVEKKRRARINESLQELRLLLAGTEVQAKLENAEVLELTVRRVQ 75
Cdd:pfam00010   1 RREAHNERERRRRDRINDAFDELRELLPTLPPDKKLSKAEILRLAIEYIK 50

basic helix-loop-helix-orange (bHLH-O) domain found in hairy and enhancer of split HES-1, HES-4 and similar proteins; The family includes two bHLH-O transcriptional repressors, HES-1 and HES-4. HES-1, also termed Class B basic helix-loop-helix protein 39 (bHLHb39), or hairy homolog, or hairy-like protein (HL), plays an essential role in development of both compartment and boundary cells of the central nervous system. It regulates the maintenance of neural stem/progenitor cells by inhibiting proneural gene expression via Notch signaling. HES-4, also termed Class B basic helix-loop-helix protein 42 (bHLHb42), or bHLH factor Hes4, antagonizes the function of Twist-1 to regulate lineage commitment of bone marrow stromal/stem cells (BMSC). Epigenetic dysregulation of HES-4 is associated with striatal degeneration in postmortem Huntington brains. Both HES-1 and HES-4 are mammalian counterparts 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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907069810  25 DRKARKPLVEKKRRARINESLQELRLLL-----AGTEVQAKLENAEVLELTVRRVQGALR 79
Cdd:cd11459     2 HRKSSKPIMEKRRRARINESLSQLKTLIldalkKDSSRHSKLEKADILEMTVKHLRNLQR 61

basic helix-loop-helix-orange (bHLH-O) domain found in hairy and enhancer of split (HES)-related repressor protein (HERP) family; HERP (also called Hey/Hesr/HRT/CHF/gridlock) proteins corresponds to a family of bHLH-O transcriptional repressors that are related to the Drosophila hairy and Enhancer-of-split proteins and act as downstream effectors of Notch signaling. They contain a basic helix-loop-helix (bHLH) domain with an invariant glycine residue in its basic region, an orange domain in the central region and YXXW sequence motif at its C-terminal region. HERP proteins are involved in cardiovascular development and have roles in somitogenesis, myogenesis and gliogenesis.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 1907069810  26 RKARKPLVEKKRRARINESLQELRLLL-AGTEVQ--AKLENAEVLELTV 71
Cdd:cd11407     1 RKKRRGIIEKRRRDRINNSLAELRRLVpTAFEKQgsAKLEKAEILQMTV 49

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
                  ....*....|....*....|....*....|....*....|....
gi 1907069810  32 LVEKKRRARINESLQELRLLL---AGTEVQAKLENAEVLELTVR 72
Cdd:cd11389     3 VIEKRRRDRINESLAELRRLVpeaRKSKGSGKLEKAEILEMTLQ 46

basic helix-loop-helix-orange (bHLH-O) domain found in Drosophila melanogaster Enhancer of split proteins, E(spl)m5, E(spl)m8 and similar proteins; The family includes two bHLH-O transcriptional repressors, E(spl)m5 and E(spl)m8, which participate in the control of cell fate choice by uncommitted neuroectodermal cells in the embryo. They bind DNA on N-box motifs, 5'-CACNAG-3'.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1907069810  27 KARKPLVEKKRRARINESLQELRLLLA---GTEVQAKLENAEVLELTV 71
Cdd:cd18916     1 KSKKPMLERQRRARINKCLSELKTLVAecsGDDGCLRMDKAEMLETAV 48

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
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1907069810  26 RKARKPLVEKKRRARINESLQELRLLLAGT---EVQAKLENAEVLELTVRRVQ 75
Cdd:cd18920    10 RKKRRGIIEKRRRDRINNSLSELRRLVPTAfekQGSAKLEKAEILQMTVDHLK 62

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 1907069810  33 VEKKRRARINESLQELRLLL---AGTEVQAKLENAEVLELTVR 72
Cdd:cd19685     1 SEKRRRQRINDKLNQLKELLppnLSKQSRSKLSKAEILEMAIT 43

Orange domain; This domain confers specificity among members of the Hairy/E(SPL) family.

                           10        20        30
                   ....*....|....*....|....*....|....
gi 1907069810   96 FAAGYIQCMHEVHTFVSTCQAIDATVSAELLNHL 129
Cdd:smart00511   3 FRSGYRECANEVSRFLSQLPGTDPDVRARLLSHL 36

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 1907069810  32 LVEKKRRARINESLQELRLLLA---GTEVQAKLENAEVLELTV 71
Cdd:cd11408     4 VIEKRRRDRINRCLNELGKTVPmalAKQTSGKLEKAEILEMTV 46

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 1907069810  34 EKKRRARINESLQELRLLLAGTEVQAKLENAEVLELTVR 72
Cdd:cd00083     1 ERRRRDKINDAFEELKRLLPELPDSKKLSKASILQKAVE 39

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in sterol regulatory element-binding protein (SREBP) family; The SREBP family includes SREBP1 and SREBP2, which are bHLHzip transcriptional activator of genes encoding proteins essential for cholesterol biosynthesis/uptake and fatty acid biosynthesis. SREBP1 and SREBP2 are principally found in the liver and in adipocytes and made up of an N-terminal transcription factor portion (composed of an activation domain, a bHLHzip domain, and a nuclear localization signal), a hydrophobic region containing two membrane spanning regions, and a C-terminal regulatory segment. They recognize a symmetric sterol regulatory element (TCACNCCAC) instead of E-box.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 1907069810  23 RGDRKARKPLVEKKRRARINESLQELRLLLAGTEvqAKLENAEVL 67
Cdd:cd11394     3 KVEKRSAHNAIEKRYRSSINDRIIELKDLVVGPD--AKMNKSAVL 45

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

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 1907069810  23 RGDRKARKPLVEKKRRARINESLQELRLLLAGTEvqAKLENAEVL 67
Cdd:cd18921     3 KGEKRTAHNAIEKRYRSSINDKIIELKDLVVGTE--AKLNKSAVL 45