helix loop helix domain;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 166295206   607 NARERLRVRDINEAFKELGRMCQLHLKSEKPqTKLLILHQAVAVILSLEQQVRE 660
Cdd:smart00353   1 NARERRRRRKINEAFDELRSLLPTLPKNKKL-SKAEILRLAIEYIKSLQEELQK 53

basic helix-loop-helix (bHLH) domain found in transcription factor 12 (TCF-12) and similar proteins; TCF-12, also termed HEB, or Class B basic helix-loop-helix protein 20 (bHLHb20), or DNA-binding protein HTF4, or E-box-binding protein, or transcription factor HTF-4, is a bHLH transcription factor that is involved in the initiation of neuronal differentiation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 166295206 602 RRMANNARERLRVRDINEAFKELGRMCQLHLKSEKPQTKLLILHQAVAVILSLEQQVRERNLNPKAACLKRREEEKVSAA 681
Cdd:cd18946    1 RRMANNARERLRVRDINEAFKELGRMCQLHLKSEKPQTKLLILHQAVAVILSLEQQVRERNLNPKAACLKRREEEKVSAV 80

                 ...
gi 166295206 682 SAE 684
Cdd:cd18946   81 SAE 83

basic helix-loop-helix (bHLH) domain found in transcription factor E47 and similar proteins; E47 is a class I bHLH transcriptional regulator that forms heterodimers with class II bHLH proteins to regulate distinct differentiation pathways. Its homodimers regulate B lymphocytes development.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 166295206 593 EQKIEREKERRMANNARERLRVRDINEAFKELGRMCQLHLKSEKPQTKLLILHQAVAVILSLEQQVRERNLNPK 666
Cdd:cd18943    1 EEKDLRDRERRMANNARERVRVRDINEAFKELGRMCQMHLKSDKAQTKLIILQQAVQVILGLEQQVRERNLNPK 74

basic helix-loop-helix (bHLH) domain found in E proteins family; The E proteins family corresponds to class I bHLH proteins, which are widely expressed within the immune system and on which the majority of this chapter will be focused. Members in this family include E2A (also referred to as TCF-3), E47, TCF-12 (also referred to as HEB), and TCF-4 (also referred to as E2-2) in vertebrates, as well as the E protein ortholog, Daughterless (Da), from Drosophila melanogaster. E-proteins are expressed broadly and in certain complexes they are restricted to specific cell types. E-proteins homodimerize and heterodimerize with the tissue specific bHLH factors to bind DNA and regulate transcription and differentiation of cells during development. The activity of the E-proteins is regulated by two main mechanisms: first, the relative concentrations of E-proteins, tissue specific bHLH factors, and the Id proteins, and second, covalent modification.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*..
gi 166295206 610 ERLRVRDINEAFKELGRMCQLHLKSEKPQTKLLILHQAVAVILSLEQ 656
Cdd:cd11420    1 ERIRVRDINEAFKELGRMCQLHLKSDKPQTKLLILHQAVSVITSLEQ 47

Helix-loop-helix DNA-binding domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 166295206  602 RRMANNARERLRVRDINEAFKELgRMCQLHLKSEKPQTKLLILHQAVAVILSLE 655
Cdd:pfam00010   1 RREAHNERERRRRDRINDAFDEL-RELLPTLPPDKKLSKAEILRLAIEYIKHLQ 53

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
                 ....*....|....*....|....*....|....*....|....*..
gi 166295206 610 ERLRVRDINEAFKELGRMCQLHLKSEKPqTKLLILHQAVAVILSLEQ 656
Cdd:cd00083    1 ERRRRDKINDAFEELKRLLPELPDSKKL-SKASILQKAVEYIRELQS 46

basic helix-loop-helix (bHLH) domain found in Drosophila melanogaster protein taxi and similar proteins; Protein taxi, also termed protein delilah (Dei), is a bHLH transcription factor that is involved in regulation of cell adhesion and attachment that is expressed in specialized cells that provide anchoring sites to either muscles (tendon cells), or proprioceptors (chordotonal attachment cells) during embryonic development. It probably plays an important role in the differentiation of epidermal cells into the tendon cells that form the attachment sites for all muscles.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 166295206 602 RRMANNARERLRVRDINEAFKELGRMCQLHLKSEKPQ--TKLLILHQAVAVILSLEQ 656
Cdd:cd11431    1 RRKTANARERDRMREINDAFEALRRAVPEYPVAGKDGklTKITTLRLAMNYIKALTD 57

basic Helix-Loop-Helix-zipper (bHLHzip) domain found in transcription factor AP-4 (TFAP4) and similar proteins; TFAP4, also termed activating enhancer-binding protein 4, or Class C basic helix-loop-helix protein 41 (bHLHc41), is a bHLHzip transcription factor that activates both viral and cellular genes involved in the regulation of cellular proliferation, stemness, and epithelial-mesenchymal transition by binding to the symmetrical DNA sequence 5'-CAGCTG-3'.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 166295206 600 KERRMANNARERLRVRDINEAFKELgRMCQLHLKSEKpQTKLLILHQAVAVILSLEQQVRE 660
Cdd:cd11419    2 RIRREIANSNERRRMQSINAGFQSL-RTLLPHCDGEK-LSKAAILQQTAEYIFSLEQEKTR 60

basic helix-loop-helix (bHLH) domain found in achaete-scute complex-like (ASCL) family; The achaete-scute complex-like (ASCL, also known as achaete-scute complex homolog or ASH) family of bHLH transcription factors, ASCL1-5, have been implicated in cell fate specification and differentiation. They are critical for proper development of the nervous system. The deregulation of ASCL plays a key role in psychiatric and neurological disorders. ASCL-1, also termed Class A basic helix-loop-helix protein 46 (bHLHa46), or achaete-scute homolog 1 (ASH-1), or mammalian achaete-scute homolog 1 (Mash1), is a neural-specific bHLH transcription factor that is expressed in subsets of neural progenitors in both the central and peripheral nervous system. It plays a key role in neuronal differentiation and specification in the nervous system. ASCL-2, also termed achaete-scute homolog 2 (ASH-2), or Class A basic helix-loop-helix protein 45 (bHLHa45), or mammalian achaete-scute homolog 2 (Mash2), is a bHLH transcription factor that is involved in Schwann cell differentiation and control of proliferation in adult peripheral nerves. ASCL-3, also termed Class A basic helix-loop-helix protein 42 (bHLHa42), or bHLH transcriptional regulator Sgn-1, or achaete-scute homolog 3 (ASH-3), is a bHLH transcription factor specifically localized in the duct cells of the salivary glands. It may act as transcriptional repressor that inhibits myogenesis. The family also includes Drosophila melanogaster achaete-scute complex (AS-C) proteins, which consists of lethal of scute (also known as achaete-scute complex protein T3 or AST3), scute (also known as achaete-scute complex protein T4 or AST4), achaete (also known as achaete-scute complex protein T5 or AST5), and asense (also known as achaete-scute complex protein T8 or AST8). They are involved in the determination of the neuronal precursors in the peripheral nervous system and the central nervous system, as well as in sex determination and dosage compensation.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 166295206 600 KERRmanNARERLRVRDINEAFKELgRMCQLHLKSEKPQTKLLILHQAVAVILSLEQQ 657
Cdd:cd11418    2 VARR---NERERRRVQAVNDAFDRL-RQHVPYLKRRKKLSKVKTLRRAIEYIRHLQKL 55

basic helix-loop-helix (bHLH) domain found in myogenic factor 5 (Myf-5) and similar proteins; Myf-5, also termed Class C basic helix-loop-helix protein 2 (bHLHc2), is a nuclear bHLH transcriptional activator that promotes transcription of muscle-specific target genes and plays a role in muscle specification and differentiation. It also acts as an RNA-binding protein which enhances Ccnd1/Cyclin D1 mRNA translation during myogenesis.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 166295206 601 ERRMANNARERLRVRDINEAFKELGRMCQLHLKSEKPqtKLLILHQAVAVILSLEQQVRER 661
Cdd:cd18937    1 DRRKAATMRERRRLKKVNQAFETLKRCTTSNPNQRLP--KVEILRNAIRYIESLQDLLREQ 59

basic helix-loop-helix (bHLH) domain found in neurogenic differentiation factor 2 (NeuroD2) and similar proteins; NeuroD2, also termed Class A basic helix-loop-helix protein 1 (bHLHa1), or NeuroD-related factor (NDRF), is a neuronal calcium-dependent bHLH transcription factor that induces neuronal differentiation and promotes neuronal survival. It plays a central role in thalamocortical synaptic maturation. NeuroD2 mediates calcium-dependent transcription activation by binding to E box-containing promoter.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 166295206 595 KIEREKERRMANNARERLRVRDINEAFKELGRMCQLHLKSEKpQTKLLILHQAVAVILSLEQQVR 659
Cdd:cd19720   28 RLERSKLRRQKANARERNRMHDLNSALDNLRKVVPCYSKTQK-LSKIETLRLAKNYIWALSEILR 91

basic helix-loop-helix (bHLH) domain found in Drosophila melanogaster myogenic-determination protein (dMYOD) and similar proteins; dMYOD, also termed protein nautilus, or Myd, may play an important role in the early development of muscle in Drosophila.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 166295206 601 ERRMANNARERLRVRDINEAFKELGRMCQLHLKSEKPqtKLLILHQAVAVILSLEQ 656
Cdd:cd19699    1 DRRKAATMRERRRLRKVNEAFEVLKRRTCPNPNQRLP--KVEILRNAIEYIESLED 54

basic helix-loop-helix (bHLH) domain found in Fer3-like protein (FERD3L), pancreas transcription factor 1 subunit alpha (PTF1A) and similar proteins; The family corresponds to a group of bHLH transcription factors, including FERD3L and PTF1A. FERD3L, also termed basic helix-loop-helix protein N-twist, or Class A basic helix-loop-helix protein 31 (bHLHa31), or nephew of atonal 3 (NATO3), or Neuronal twist (NTWIST), is expressed in the developing central nervous system (CNS). It regulates floor plate (FP) cells development. FP is a critical organizing center located at the ventral-most midline of the neural tube. FERD3L binds to the E-box and functions as inhibitor of transcription. PTF1A, also termed Class A basic helix-loop-helix protein 29 (bHLHa29), or pancreas-specific transcription factor 1a, or bHLH transcription factor p48, or p48 DNA-binding subunit of transcription factor PTF1 (PTF1-p48), is implicated in the cell fate determination in various organs. It binds to the E-box consensus sequence 5'-CANNTG-3' and plays a role in early and late pancreas development and differentiation.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 166295206 601 ERRMANNaRERLRVRDINEAFKELgRMCQLHLKSEKPQTKLLILHQAVAVI 651
Cdd:cd19686    1 QRQAANI-RERKRMRSINDAFDGL-RRHIPTFPYEKRLSKVDTLRLAIQYI 49

basic helix-loop-helix (bHLH) domain found in muscle, intestine and stomach expression 1 (MIST-1) and similar proteins; MIST-1, also termed Class A basic helix-loop-helix protein 15 (bHLHa15), or Class B basic helix-loop-helix protein 8 (bHLHb8), is a bHLH transcription factor expressed in pancreatic acinar cells and other serous exocrine cells. It is essential for cytoskeletal organization and secretory activity. It also functions as a potent endoplasmic reticulum (ER) stress-inducible transcriptional regulator. MIST-1 is capable of binding to E-box (CANNTG) motifs as a homodimer or a heterodimer with E-proteins (E12 and E47) to regulate transcription.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 166295206 602 RRMANNARERLRVRDINEAFKELgRMCQLHLKSEKPQTKLLILHQAVAVILSL 654
Cdd:cd19711    1 RRLESNERERQRMHKLNNAFQAL-REVIPHVRAEKKLSKIETLTLAKNYIKSL 52

basic helix-loop-helix (bHLH) domain found in Drosophila melanogaster helix loop helix protein 3B (dHLH3B) and similar proteins; Drosophila HLH3B is an uncharacterized bHLH transcription factor that belongs to the T-cell acute lymphocytic leukemia protein/ lymphoblastic leukemia-derived sequence (TAL/LYL) family.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 166295206 602 RRMANNARERLRVRDINEAFKELGRMCQLHlKSEKPQTKLLILHQAVAVILSLEQQVR 659
Cdd:cd19708    1 RRMFTNSRERWRQQNVNGAFAELRKLVPTH-PPDKKLSKNEILRLAIKYIRLLSNVLE 57

basic helix-loop-helix (bHLH) domain found in myogenic regulatory factor (MRF) family; MRFs are a family of muscle-specific bHLH transcription proteins (MyoD, Myf5, Mrf4 and MyoG) that plays an essential role in regulating skeletal muscle development and growth. MRFs are capable of binding to E-box motifs as a heterodimer with E-proteins to regulate transcription expression.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 166295206 601 ERRMANNARERLRVRDINEAFKELGRMCQLHLKSEKPqtKLLILHQAVAVILSLE 655
Cdd:cd11411    1 DRRKAATMRERRRLKKVNEAFEALKRCTSANPNQRLP--KVEILRNAIEYIESLQ 53

basic helix-loop-helix (bHLH) domain found in myoblast determination protein 1 (MYOD1) and similar proteins; MYOD1, also termed Class C basic helix-loop-helix protein 1 (bHLHc1), or myogenic factor 3 (Myf-3), is a bHLH transcriptional activator that promotes transcription of muscle-specific target genes and plays a role in muscle differentiation. Together with Myf-5 and MYOG, MYOD1 co-occupies muscle-specific gene promoter core region during myogenesis.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 166295206 601 ERRMANNARERLRVRDINEAFKELGRMCQLHLKSEKPqtKLLILHQAVAVILSLEQQVR 659
Cdd:cd18936    5 DRRKAATMRERRRLSKVNEAFETLKRCTSTNPNQRLP--KVEILRNAIRYIESLQALLR 61

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 166295206 606 NNARERLRvRD-INEAFKELGRM---CQLHLKSEKPqTKLLILHQAVAVILSLEQQVRE 660
Cdd:cd11387    2 HNAVERRR-RDnINEKIQELGSLvppSRLETKDLKP-NKGSILSKAVEYIRELQNQNQE 58