helix loop helix domain;

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 2462567181  501 NARERVRVRDINEAFRELGRMCQMHLKSDKaQTKLLILQQAVQVILGLEQQVRE 554
Cdd:smart00353   1 NARERRRRRKINEAFDELRSLLPTLPKNKK-LSKAEILRLAIEYIKSLQEELQK 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 2462567181 492 RDRERRMANNARERVRVRDINEAFRELGRMCQMHLKSDKAQTKLLILQQAVQVILGLEQQVRERNLNPKAACLKRREEEK 571
Cdd:cd18945     4 REKERRMANNARERLRVRDINEAFKELGRMVQLHLKSDKPQTKLLILHQAVAVILSLEQQVRERNLNPKAACLKRREEEK 83

                  ..
gi 2462567181 572 VS 573
Cdd:cd18945    84 VS 85

basic helix-loop-helix (bHLH) domain found in transcription factor E2-alpha (E2A) and similar proteins; E2A, also termed Class B basic helix-loop-helix protein 21 (bHLHb21), or immunoglobulin enhancer-binding factor E12/E47, or immunoglobulin transcription factor 1, or Kappa-E2-binding factor, or transcription factor 3 (TCF-3), or transcription factor ITF-1, is a bHLH transcriptional regulator involved in the initiation of neuronal differentiation.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2462567181 495 ERRMANNARERVRVRDINEAFRELGRMCQMHLKSDKAQTKLLILQQAVQVILGLEQQVRERNLNPKAACLKRRE 568
Cdd:cd18944     1 ERRVANNARERLRVRDINEAFKELGRMCQLHLNSEKPQTKLLILHQAVSVILNLEQQVRERNLNPKAACLKRRE 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 2462567181 504 ERVRVRDINEAFRELGRMCQMHLKSDKAQTKLLILQQAVQVILGLEQ 550
Cdd:cd11420     1 ERIRVRDINEAFKELGRMCQLHLKSDKPQTKLLILHQAVSVITSLEQ 47

Helix-loop-helix DNA-binding domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 2462567181 496 RRMANNARERVRVRDINEAFRELGRMCQmHLKSDKAQTKLLILQQAVQVILGLE 549
Cdd:pfam00010   1 RREAHNERERRRRDRINDAFDELRELLP-TLPPDKKLSKAEILRLAIEYIKHLQ 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 2462567181 496 RRMANNARERVRVRDINEAFRELgRMC--QMHLKSDKAQ-TKLLILQQAVQVILGLEQ 550
Cdd:cd11431     1 RRKTANARERDRMREINDAFEAL-RRAvpEYPVAGKDGKlTKITTLRLAMNYIKALTD 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 2462567181 504 ERVRVRDINEAFRELGRMCQMHLKSDKaQTKLLILQQAVQVILGLEQ 550
Cdd:cd00083     1 ERRRRDKINDAFEELKRLLPELPDSKK-LSKASILQKAVEYIRELQS 46

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 2462567181 493 DRERRmanNARERVRVRDINEAFRELgRMCQMHLKSDKAQTKLLILQQAVQVILGLEQQ 551
Cdd:cd11418     1 RVARR---NERERRRVQAVNDAFDRL-RQHVPYLKRRKKLSKVKTLRRAIEYIRHLQKL 55

basic helix-loop-helix (bHLH) domain found in protein atonal homolog 7 (ATOH7) and similar proteins; ATOH7, also termed Class A basic helix-loop-helix protein 13 (bHLHa13), or helix-loop-helix protein hATH-5 (hATH5), or Math5, is a bHLH transcription factor involved in the differentiation of retinal ganglion cells.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 2462567181 494 RERRMANNARERVRVRDINEAFRELGRMCQmHLKSDKAQTKLLILQQAVQVILGL 548
Cdd:cd19714     6 ARRRLAANARERRRMQGLNTAFDRLRKVVP-QWGQDKKLSKYETLQMALSYIMAL 59

basic helix-loop-helix (bHLH) domain found in protein atonal homolog 1 (ATOH1) and similar proteins; ATOH1, also termed Class A basic helix-loop-helix protein 14 (bHLHa14), or helix-loop-helix protein hATH-1 (hATH1), or Math1, or Cath1, is a proneural bHLH transcription factor that is essential for inner ear hair cell differentiation. It dimerizes with E47 and activates E-box (CANNTG) dependent transcription. ATOH1 is a mammalian homolog of the Drosophila melanogaster gene atonal and mouse atonal homolog 1 (Math1).

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 2462567181 494 RERRMANNARERVRVRDINEAFRELgRMCQMHLKSDKAQTKLLILQQA 541
Cdd:cd19713     4 KQRRLAANARERRRMHGLNHAFDQL-RNVIPSFNNDKKLSKYETLQMA 50

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 2462567181 495 ERRMANNaRERVRVRDINEAFRELgRMCQMHLKSDKAQTKLLILQQAVQVI 545
Cdd:cd19686     1 QRQAANI-RERKRMRSINDAFDGL-RRHIPTFPYEKRLSKVDTLRLAIQYI 49

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 2462567181 496 RRMANNARERVRVRDINEAFRELGRMCQMHlKSDKAQTKLLILQQAVQVILGLEQQVR 553
Cdd:cd19708     1 RRMFTNSRERWRQQNVNGAFAELRKLVPTH-PPDKKLSKNEILRLAIKYIRLLSNVLE 57

RecF/RecN/SMC N terminal domain; This domain is found at the N terminus of SMC proteins. The SMC (structural maintenance of chromosomes) superfamily proteins have ATP-binding domains at the N- and C-termini, and two extended coiled-coil domains separated by a hinge in the middle. The eukaryotic SMC proteins form two kind of heterodimers: the SMC1/SMC3 and the SMC2/SMC4 types. These heterodimers constitute an essential part of higher order complexes, which are involved in chromatin and DNA dynamics. This family also includes the RecF and RecN proteins that are involved in DNA metabolism and recombination.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462567181  444 SEIKREEKEDEENTSAADHSEEEKKELKAPRA-RTSSTDEVLSLEEKDLRDRERRMANNARERVRvrdINEAFRELgrmc 522
Cdd:pfam02463  321 KEKKKAEKELKKEKEEIEELEKELKELEIKREaEEEEEEELEKLQEKLEQLEEELLAKKKLESER---LSSAAKLK---- 393

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*....
gi 2462567181  523 qmhlksDKAQTKLLILQQAVQVILGLEQQVRERNLNPKAACLKRREEEK 571
Cdd:pfam02463  394 ------EEELELKSEEEKEAQLLLELARQLEDLLKEEKKEELEILEEEE 436

basic helix-loop-helix (bHLH) domain found in helix-loop-helix protein 1 (HEN-1) and similar proteins; HEN-1, also termed nescient helix-loop-helix 1 (Nhlh1), or Class A basic helix-loop-helix protein 35 (bHLHa35), or nescient helix loop helix 1 (NSCL-1), is a neuron-specific bHLH transcription factor that may serve as DNA-binding protein and may be involved in the control of cell-type determination, possibly within the developing nervous system.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2462567181 484 LSLEEKDLRDR---ERRMANNARERVRVRDINEAFRELGRMCQMhLKSDKAQTKLLILQQAVQVI 545
Cdd:cd19701     1 LSREERRRRRRataKYRTAHATRERIRVEAFNVAFAELRKLLPT-LPPDKKLSKIEILRLAICYI 64

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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462567181 452 EDEENTSAADhSEEEKKELKAPRARTSSTDEvlsleekdlRDRERRMANNARERVRVRDINEAFRELGRMCQMHLKSDKA 531
Cdd:cd19720     1 EEEEGLEEAD-GERPKKRGPKKRKMTKARLE---------RSKLRRQKANARERNRMHDLNSALDNLRKVVPCYSKTQKL 70

                          90       100
                  ....*....|....*....|..
gi 2462567181 532 qTKLLILQQAVQVILGLEQQVR 553
Cdd:cd19720    71 -SKIETLRLAKNYIWALSEILR 91

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 2462567181 496 RRMANNARERVRVRDINEAFRELGRMCQMHlKSDKAQTKLLILQQAVQVILGLE 549
Cdd:cd11413     1 RRIFTNTRERWRQQNVNGAFAELRKLIPTH-PPDKKLSKNEILRLAMKYIKFLE 53

basic helix-loop-helix (bHLH) domain found in T-cell acute lymphocytic leukemia protein 2 (TAL-2) and similar proteins; TAL-2, also termed Class A basic helix-loop-helix protein 19 (bHLHa19), is a bHLH transcription factor essential for the normal brain development. It has been implicated in T-cell acute lymphoblastic leukemia.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 2462567181 496 RRMANNARERVRVRDINEAFRELGRMCQMHlKSDKAQTKLLILQQAVQVI 545
Cdd:cd19707     2 RKIFTNTRERWRQQNVNSAFAELRKLIPTH-PPDKKLSKNEILRLAMKYI 50

basic helix-loop-helix (bHLH) domain found in T-cell acute lymphocytic leukemia protein 1 (TAL-1) and similar proteins; 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-1 has been implicated in T-cell acute lymphoblastic leukemia. In common with other tissue-specific bHLH proteins, Tal heterodimerizes with ubiquitously-expressed members of the E2A family and form a DNA-binding complex with an E-box (CANNTG) to regulate transcription at its recognition site.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 2462567181 496 RRMANNARERVRVRDINEAFRELGRMCQMHlKSDKAQTKLLILQQAVQVI 545
Cdd:cd19706     4 RRIFTNSRERWRQQNVNGAFAELRKLIPTH-PPDKKLSKNEILRLAMKYI 52

basic helix-loop-helix (bHLH) domain found in Drosophila melanogaster achaete-scute complex (AS-C) proteins, achaete-scute-like proteins, ASCL1-2, and similar proteins; This subfamily includes Drosophila melanogaster AS-C proteins and two ASCL family of transcription factors, ASCL-1 and ASCL-2. Drosophila melanogaster AS-C proteins includes 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. 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 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 involved in Schwann cell differentiation and control of proliferation in adult peripheral nerves.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 2462567181 501 NARERVRVRDINEAFRELgRMCQMHLKSDKAQTKLLILQQAVQVILGLEQ 550
Cdd:cd19723     6 NERERNRVKLVNLGFATL-REHVPNGRANKKMSKVETLRSAVEYIRQLQQ 54

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 2462567181 500 NNARERVRvRD-INEAFRELGRM---CQMHLKsDKAQTKLLILQQAVQVILGLEQQVRE 554
Cdd:cd11387     2 HNAVERRR-RDnINEKIQELGSLvppSRLETK-DLKPNKGSILSKAVEYIRELQNQNQE 58