helix loop helix domain;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 17137250    560 NARERIRIRDINEALKELGRMCMTHLKSDKPqTKLGILNMAVEVIMTLEQQVRE 613
Cdd:smart00353   1 NARERRRRRKINEAFDELRSLLPTLPKNKKL-SKAEILRLAIEYIKSLQEELQK 53

basic helix-loop-helix (bHLH) domain found in transcription factor 4 (TCF-4) and similar proteins; TCF-4, also termed E2-2, or Class B basic helix-loop-helix protein 19 (bHLHb19), or immunoglobulin transcription factor 2 (ITF-2), or SL3-3 enhancer factor 2 (SEF-2), is a bHLH transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5-motif. It is involved in the initiation of neuronal differentiation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17137250 548 KAIREKERRQANNARERIRIRDINEALKELGRMCMTHLKSDKPQTKLGILNMAVEVIMTLEQQVRERNLNPKAACLKRRE 627
Cdd:cd18945   1 KAEREKERRMANNARERLRVRDINEAFKELGRMVQLHLKSDKPQTKLLILHQAVAVILSLEQQVRERNLNPKAACLKRRE 80

                ...
gi 17137250 628 EEK 630
Cdd:cd18945  81 EEK 83

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 17137250 555 RRQANNARERIRIRDINEALKELGRMCMTHLKSDKPQTKLGILNMAVEVIMTLEQQVRERNLNPKAACLKRREEEKA 631
Cdd:cd18946   1 RRMANNARERLRVRDINEAFKELGRMCQLHLKSEKPQTKLLILHQAVAVILSLEQQVRERNLNPKAACLKRREEEKV 77

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 17137250 563 ERIRIRDINEALKELGRMCMTHLKSDKPQTKLGILNMAVEVIMTLEQ 609
Cdd:cd11420   1 ERIRVRDINEAFKELGRMCQLHLKSDKPQTKLLILHQAVSVITSLEQ 47

Helix-loop-helix DNA-binding domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 17137250   555 RRQANNARERIRIRDINEALKELgRMCMTHLKSDKPQTKLGILNMAVEVIMTLE 608
Cdd:pfam00010   1 RREAHNERERRRRDRINDAFDEL-RELLPTLPPDKKLSKAEILRLAIEYIKHLQ 53

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 17137250 555 RRQANNARERIRIRDINEALKELGRM--CMTHLKSDKPQTKLGILNMAVEVIMTLEQ 609
Cdd:cd11431   1 RRKTANARERDRMREINDAFEALRRAvpEYPVAGKDGKLTKITTLRLAMNYIKALTD 57

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
                ....*....|....*....|....*....|....*....|....*....
gi 17137250 556 RQANNARERIRIRDINEALKELgRMCMTHLKSDKPQTKLGILNMAVEVI 604
Cdd:cd19686   2 RQAANIRERKRMRSINDAFDGL-RRHIPTFPYEKRLSKVDTLRLAIQYI 49

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 17137250 553 KERRqanNARERIRIRDINEALKELgRMCMTHLKSDKPQTKLGILNMAVEVIMTLEQQ 610
Cdd:cd11418   2 VARR---NERERRRVQAVNDAFDRL-RQHVPYLKRRKKLSKVKTLRRAIEYIRHLQKL 55

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 17137250 551 REKERRQANNARERIRIRDINEALKELGRMCMTHLKSDKpQTKLGILNMAVEVIMTLEQQVR 612
Cdd:cd19720  31 RSKLRRQKANARERNRMHDLNSALDNLRKVVPCYSKTQK-LSKIETLRLAKNYIWALSEILR 91

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 17137250 553 KERRQANNARERIRIRDINEALKELgRMCMTHLKSDKpQTKLGILNMAVEVIMTLEQQVRE 613
Cdd:cd11419   2 RIRREIANSNERRRMQSINAGFQSL-RTLLPHCDGEK-LSKAAILQQTAEYIFSLEQEKTR 60

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 17137250 554 ERRQANNARERIRIRDINEALKELGRMCMTHLKSDKPqtKLGILNMAVEVIMTLEQQVRER 614
Cdd:cd18937   1 DRRKAATMRERRRLKKVNQAFETLKRCTTSNPNQRLP--KVEILRNAIRYIESLQDLLREQ 59

basic helix-loop-helix (bHLH) domain found in neurogenic differentiation factor 6 (NeuroD6) and similar proteins; NeuroD6, also termed Class A basic helix-loop-helix protein 2 (bHLHa2), or protein atonal homolog 2 (ATH-2), or Atoh2, or Math2, or Nex1, is a neurogenic bHLH transcription factor involved in neuronal development, differentiation, and survival in Alzheimer's disease (AD) brains of both cohorts. It plays an integrative role in coordinating increase in mitochondrial mass with cytoskeletal remodeling, suggesting that it may act as a co-regulator of neuronal differentiation and energy metabolism.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 17137250 551 REKERRQANNARERIRIRDINEALKELGRMCMTHLKSDKpQTKLGILNMAVEVIMTLEQQVR 612
Cdd:cd19722  10 RVKVRRQEANARERNRMHGLNDALDSLRKVVPCYSKTQK-LSKIETLRLAKNYIWALSEILR 70

basic helix-loop-helix (bHLH) domain found in muscle, intestine and stomach expression 1 (MIST-1) family; 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. The family also includes Drosophila melanogaster protein dimmed and similar proteins. Dimmed, also termed DIMM, is a bHLH transcription factor that regulates neurosecretory (NS) cell function and neuroendocrine cell fate in Drosophila.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 17137250 555 RRQANNARERIRIRDINEALKELGRMCmTHLKSDKPQTKLGILNMAVEVIMTL 607
Cdd:cd11426   1 RRLESNERERLRMHQLNDAFQALREVI-PHVRSERKLSKIETLTLAKNYIKSL 52

basic helix-loop-helix (bHLH) domain found in neurogenin (NGN) family; The NGN family includes three neural-specific bHLH transcription factors, NGN1-3, which may function at neuroblast selection genes during the development of several neuronal lineages. NGN-1, also termed Class A basic helix-loop-helix protein 6 (bHLHa6), or neurogenic basic-helix-loop-helix protein, or neurogenic differentiation factor 3 (NeuroD3), is a neural-specific bHLH transcription factor involved in the initiation of neuronal differentiation. NGN-2, also termed Class A basic helix-loop-helix protein 8 (bHLHa8), or protein atonal homolog 4 (ATOH4), is a neural-specific bHLH transcription factor required for sensory neurogenesis. NGN-3, also termed Class A basic helix-loop-helix protein 7 (bHLHa7), or protein atonal homolog 5 (ATOH5), is a neural-specific bHLH transcription factor expressed in the developing central nervous system and the embryonic pancreas. It is involved in neurogenesis and plays an important role in spermatogenesis.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 17137250 555 RRQANNARERIRIRDINEALKELgRMCMTHLKSDKPQTKLGILNMAVEVIMTLEQQVR 612
Cdd:cd11428   1 RRLKANDRERNRMHNLNDALDAL-REVLPSFPDETKLTKIETLRFAHNYIWALSETLK 57

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 17137250 563 ERIRIRDINEALKELGRMCMTHLKSDKPqTKLGILNMAVEVIMTLEQ 609
Cdd:cd00083   1 ERRRRDKINDAFEELKRLLPELPDSKKL-SKASILQKAVEYIRELQS 46

basic helix-loop-helix (bHLH) domain found in Drosophila melanogaster protein dimmed and similar proteins; Dimmed, also termed DIMM, is a bHLH transcription factor that regulates neurosecretory (NS) cell function and neuroendocrine cell fate in Drosophila.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 17137250 555 RRQANNARERIRIRDINEALKELgRMCMTHLKSDKPQTKLGILNMAVEVIMTL 607
Cdd:cd19712   1 RRLESNERERMRMHSLNDAFQGL-REVIPHVNAERKLSKIETLTLAKNYIKAL 52

basic helix-loop-helix (bHLH) domain found in T-cell acute lymphocytic leukemia protein/ lymphoblastic leukemia-derived sequence (TAL/LYL) family; The TAL/LYL family includes a group of bHLH transcription factors (TAL1, TAL2 and LYL1) implicated in T cell acute leukaemia. They act as mediators of T cell leukaemogenesis. TAL-1, also termed Class A basic helix-loop-helix protein 17 (bHLHa17), or stem cell protein (SCL), or T-cell leukemia/lymphoma protein 5, is a hematopoietic-specific bHLH transcription factor that functions in embryonic and adult hematopoiesis in vertebrates. It is also required for embryonic vascular remodeling. It acts as a regulator of erythroid differentiation and binds to regulatory regions of a large cohort of erythroid genes as part of a complex with GATA-1, LMO2 and Ldb1. TAL-2, also termed Class A basic helix-loop-helix protein 19 (bHLHa19), is a bHLH transcription factor essential for the normal brain development. Lyl-1, also termed Class A basic helix-loop-helix protein 18 (bHLHa18), or lymphoblastic leukemia-derived sequence 1, is a proto-oncogenic bHLH transcription factor that plays an important role in hematopoietic stem cell function and is required for the late stages of postnatal angiogenesis to limit the formation of new blood vessels, notably by regulating the activity of the small GTPase Rap1. LYL-1 deficiency induces a stress erythropoiesis.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 17137250 555 RRQANNARERIRIRDINEALKELGRMCMTHlKSDKPQTKLGILNMAVEVIMTLE 608
Cdd:cd11413   1 RRIFTNTRERWRQQNVNGAFAELRKLIPTH-PPDKKLSKNEILRLAMKYIKFLE 53

basic helix-loop-helix (bHLH) domain found in Caenorhabditis elegans Helix-loop-helix protein 13 (HLH13) and similar proteins; Caenorhabditis elegans HLH13, also termed Fer3-like protein, or nephew of atonal 3, is a bHLH transcription factor that plays a role in the negative regulation of exit from L1 arrest and dauer diapause dependent on IIS signaling (insulin and insulin-like growth factor (IGF) signaling).

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 17137250 552 EKERRQANNARERIRIRDINEALKELgRMCMTHLKSDKPQTKLGILNMAVEVIMTL 607
Cdd:cd11416   2 YKVQRHAANIRERKRMLSINSAFEEL-RCHVPTFPYEKRLSKIDTLRLAIAYIALL 56