Not to be confused with helix-turn-helix domains, a motif similar in shape and function.
A basic helix–loop–helix (bHLH) is a proteinstructural motif that characterizes one of the largest families of dimerizing transcription factors.[2][3][4][5] The word "basic" does not refer to complexity but to the chemistry of the motif because transcription factors in general contain basicamino acid residues in order to facilitate DNA binding.[6]
Basic helix–loop–helix DNA-binding domain
Basic helix–loop–helix structural motif of ARNT. Two α-helices (blue) are connected by a short loop (red).[1]
bHLH transcription factors are often important in development or cell activity. For one, BMAL1-Clock (also called ARNTL) is a core transcription complex in the molecular circadian clock. Other genes, like c-Myc and HIF-1, have been linked to cancer due to their effects on cell growth and metabolism.
The motif is characterized by two α-helices connected by a loop. In general, transcription factors (including this type) are dimeric, each with one helix containing basicamino acid residues that facilitate DNA binding.[6] In general, one helix is smaller, and due to the flexibility of this loop, allows dimerization by folding and packing against another helix. The larger helix typically contains the DNA-binding regions. bHLH proteins typically bind to a consensus sequence called an E-box, CANNTG.[7] The canonical E-box is CACGTG (palindromic), however some bHLH transcription factors, notably those of the bHLH-PAS family, bind to related non-palindromic sequences, which are similar to the E-box. bHLH TFs may homodimerize or heterodimerize with other bHLH TFs and form a large variety of dimers, each one with specific functions.[8]
Examplesedit
A phylogenetic analysis suggested that bHLH proteins fall into 6 major groups, indicated by letters A through F. [9] Examples of transcription factors containing a bHLH include:
Since many bHLH transcription factors are heterodimeric,[8] their activity is often highly regulated by the dimerization of the subunits. One subunit's expression or availability is often controlled, whereas the other subunit is constitutively expressed. Many of the known regulatory proteins, such as the Drosophilaextramacrochaetae protein, have the helix-loop-helix structure but lack the basic region, making them unable to bind to DNA on their own. They are, however, able to form heterodimers with proteins that have the bHLH structure, and inactivate their abilities as transcription factors.[10]
Historyedit
1989: Murre et al. showed that dimers of various bHLH proteins bind to a short DNA motif (later called E-Box).[11] This E-box consists of the DNA sequence CANNTG, where N can be any nucleotide.[7]
1994: Harrison's[12] and Pabo's[13] groups crystallize bHLH proteins bound to E-boxes, demonstrating that the parallel 4-helix bundle motif loop orients the basic sequences to interact with specific nucleotides in the major groove of the E-box.
1994: Wharton et al. identified asymmetric E-boxes bound by a subset of bHLH proteins with PAS domains (bHLH-PAS proteins), including Single-minded (Sim) and the aromatic hydrocarbon receptor.[14]
1995: Semenza's group identifies hypoxia-inducible factor (HIF) as a bHLH-PAS heterodimer that binds a related asymmetric E-box.[15]
2009: Grove, De Masi et al., identified novel short DNA motifs, bound by a subset of bHLH proteins, which they defined as "E-box-like sequences". These are in the form of CAYRMK, where Y stands for C or T, R is A or G, M is A or C and K is G or T.[16]
Human proteins with helix–loop–helix DNA-binding domainedit
^PDB: 1x0o; Card PB, Erbel PJ, Gardner KH (October 2005). "Structural basis of ARNT PAS-B dimerization: use of a common beta-sheet interface for hetero- and homodimerization". J. Mol. Biol. 353 (3): 664–77. doi:10.1016/j.jmb.2005.08.043. PMID 16181639.
^Murre C, Bain G, van Dijk MA, Engel I, Furnari BA, Massari ME, Matthews JR, Quong MW, Rivera RR, Stuiver MH (June 1994). "Structure and function of helix-loop-helix proteins". Biochim. Biophys. Acta. 1218 (2): 129–35. doi:10.1016/0167-4781(94)90001-9. PMID 8018712.
^Littlewood TD, Evan GI (1995). "Transcription factors 2: helix-loop-helix". Protein Profile. 2 (6): 621–702. PMID 7553065.
^Massari ME, Murre C (January 2000). "Helix-loop-helix proteins: regulators of transcription in eucaryotic organisms". Mol. Cell. Biol. 20 (2): 429–40. doi:10.1128/MCB.20.2.429-440.2000. PMC85097. PMID 10611221.
^Amoutzias, Grigoris D.; Robertson, David L.; Van de Peer, Yves; Oliver, Stephen G. (2008-05-01). "Choose your partners: dimerization in eukaryotic transcription factors". Trends in Biochemical Sciences. 33 (5): 220–229. doi:10.1016/j.tibs.2008.02.002. ISSN 0968-0004. PMID 18406148.
^ abLawrence Zipursky; Arnold Berk; Monty Krieger; Darnell, James E.; Lodish, Harvey F.; Kaiser, Chris; Matthew P Scott; Matsudaira, Paul T. (2003-08-22). McGill Lodish 5E Package - Molecular Cell Biology & McGill Activation Code. San Francisco: W. H. Freeman. ISBN0-7167-8635-4.
^ abChaudhary J, Skinner MK (1999). "Basic helix-loop-helix proteins can act at the E-box within the serum response element of the c-fos promoter to influence hormone-induced promoter activation in Sertoli cells". Mol. Endocrinol. 13 (5): 774–86. doi:10.1210/mend.13.5.0271. PMID 10319327.
^ abAmoutzias, Gregory D.; Robertson, David L.; Oliver, Stephen G.; Bornberg-Bauer, Erich (2004-03-01). "Convergent evolution of gene networks by single-gene duplications in higher eukaryotes". EMBO Reports. 5 (3): 274–279. doi:10.1038/sj.embor.7400096. ISSN 1469-221X. PMC1299007. PMID 14968135.
^Ledent, V; Paquet, O; Vervoort, M (2002). "Phylogenetic analysis of the human basic helix-loop-helix proteins". Genome Biology. 3 (6): research0030.1. doi:10.1186/gb-2002-3-6-research0030. PMC116727. PMID 12093377.
^Cabrera CV, Alonso MC, Huikeshoven H (1994). "Regulation of scute function by extramacrochaete in vitro and in vivo". Development. 120 (12): 3595–603. doi:10.1242/dev.120.12.3595. PMID 7821225.
^Murre C, McCaw PS, Vaessin H, et al. (1989). "Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence". Cell. 58 (3): 537–44. doi:10.1016/0092-8674(89)90434-0. PMID 2503252. S2CID 29339773.
^Ellenberger T, Fass D, Arnaud M, Harrison SC (April 1994). "Crystal structure of transcription factor E47: E-box recognition by a basic region helix-loop-helix dimer". Genes Dev. 8 (8): 970–80. doi:10.1101/gad.8.8.970. PMID 7926781.
^Ma PC, Rould MA, Weintraub H, Pabo CO (May 1994). "Crystal structure of MyoD bHLH domain-DNA complex: perspectives on DNA recognition and implications for transcriptional activation". Cell. 77 (3): 451–9. doi:10.1016/0092-8674(94)90159-7. PMID 8181063. S2CID 44902701.
^Wharton KA, Franks RG, Kasai Y, Crews ST (December 1994). "Control of CNS midline transcription by asymmetric E-box-like elements: similarity to xenobiotic responsive regulation". Development. 120 (12): 3563–9. doi:10.1242/dev.120.12.3563. PMID 7821222.
^Wang GL, Jiang BH, Rue EA, Semenza GL (June 1995). "Hypoxia-inducible factor 1 is a basic helix-loop-helix-PAS heterodimer regulated by cellular O2 tension". Proc. Natl. Acad. Sci. U.S.A. 92 (12): 5510–4. Bibcode:1995PNAS...92.5510W. doi:10.1073/pnas.92.12.5510. PMC41725. PMID 7539918.
^Grove C, De Masi F, et al. (2009). "A multiparameter network reveals extensive divergence between C. elegans bHLH transcription factors". Cell. 138 (2): 314–27. doi:10.1016/j.cell.2009.04.058. PMC2774807. PMID 19632181.
Basic+Helix-Loop-Helix+Transcription+Factors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
bHLH family 2016-04-22 at the Wayback Machine at PlantTFDB:Plant Transcription Factor Database
April 26, 2024
basic, helix, loop, helix, confused, with, helix, turn, helix, domains, motif, similar, shape, function, basic, helix, loop, helix, bhlh, protein, structural, motif, that, characterizes, largest, families, dimerizing, transcription, factors, word, basic, does,. Not to be confused with helix turn helix domains a motif similar in shape and function A basic helix loop helix bHLH is a protein structural motif that characterizes one of the largest families of dimerizing transcription factors 2 3 4 5 The word basic does not refer to complexity but to the chemistry of the motif because transcription factors in general contain basic amino acid residues in order to facilitate DNA binding 6 Basic helix loop helix DNA binding domainBasic helix loop helix structural motif of ARNT Two a helices blue are connected by a short loop red 1 IdentifiersSymbolbHLHPfamPF00010InterProIPR001092SMARTSM00353PROSITEPDOC00038SCOP21mdy SCOPe SUPFAMCDDcd00083Available protein structures Pfam structures ECOD PDBRCSB PDB PDBe PDBjPDBsumstructure summaryPDB1a0a 1am9 1an2 1an4 1hlo 1mdy 1nkp 1nlw 1r05 1ukl 2ql2 bHLH transcription factors are often important in development or cell activity For one BMAL1 Clock also called ARNTL is a core transcription complex in the molecular circadian clock Other genes like c Myc and HIF 1 have been linked to cancer due to their effects on cell growth and metabolism Contents 1 Structure 2 Examples 2 1 Group A 2 2 Group B 2 3 Group C 2 4 Group D 2 5 Group E 2 6 Group F 3 Regulation 4 History 5 Human proteins with helix loop helix DNA binding domain 6 See also 7 References 8 External linksStructure editThe motif is characterized by two a helices connected by a loop In general transcription factors including this type are dimeric each with one helix containing basic amino acid residues that facilitate DNA binding 6 In general one helix is smaller and due to the flexibility of this loop allows dimerization by folding and packing against another helix The larger helix typically contains the DNA binding regions bHLH proteins typically bind to a consensus sequence called an E box CANNTG 7 The canonical E box is CACGTG palindromic however some bHLH transcription factors notably those of the bHLH PAS family bind to related non palindromic sequences which are similar to the E box bHLH TFs may homodimerize or heterodimerize with other bHLH TFs and form a large variety of dimers each one with specific functions 8 Examples editA phylogenetic analysis suggested that bHLH proteins fall into 6 major groups indicated by letters A through F 9 Examples of transcription factors containing a bHLH include Group A edit MyoD Myf5 Beta2 NeuroD1 Scl also known as Tal1 proneural bHLH genes like p CaMKII and pSer 336 NeuroD Neurogenins Group B edit MAX C Myc N Myc TCF4 Transcription Factor 4 Group C edit These proteins contain two additional PAS domains after the bHLH domain AhR BMAL 1 CLOCK HIF NPAS1 NPAS3 MOP5 Group D edit EMC Group E edit HEY1 and HEY2 Group F edit These proteins contain an additional COE domain EBF1Regulation editSince many bHLH transcription factors are heterodimeric 8 their activity is often highly regulated by the dimerization of the subunits One subunit s expression or availability is often controlled whereas the other subunit is constitutively expressed Many of the known regulatory proteins such as the Drosophila extramacrochaetae protein have the helix loop helix structure but lack the basic region making them unable to bind to DNA on their own They are however able to form heterodimers with proteins that have the bHLH structure and inactivate their abilities as transcription factors 10 History edit1989 Murre et al showed that dimers of various bHLH proteins bind to a short DNA motif later called E Box 11 This E box consists of the DNA sequence CANNTG where N can be any nucleotide 7 1994 Harrison s 12 and Pabo s 13 groups crystallize bHLH proteins bound to E boxes demonstrating that the parallel 4 helix bundle motif loop orients the basic sequences to interact with specific nucleotides in the major groove of the E box 1994 Wharton et al identified asymmetric E boxes bound by a subset of bHLH proteins with PAS domains bHLH PAS proteins including Single minded Sim and the aromatic hydrocarbon receptor 14 1995 Semenza s group identifies hypoxia inducible factor HIF as a bHLH PAS heterodimer that binds a related asymmetric E box 15 2009 Grove De Masi et al identified novel short DNA motifs bound by a subset of bHLH proteins which they defined as E box like sequences These are in the form of CAYRMK where Y stands for C or T R is A or G M is A or C and K is G or T 16 Human proteins with helix loop helix DNA binding domain editAHR AHRR ARNT ARNT2 ARNTL ARNTL2 ASCL1 ASCL2 ASCL3 ASCL4 ATOH1 ATOH7 ATOH8 BHLHB2 BHLHB3 BHLHB4 BHLHB5 BHLHB8 CLOCK EPAS1 FERD3L FIGLA HAND1 HAND2 HES1 HES2 HES3 HES4 HES5 HES6 HES7 HEY1 HEY2 HIF1A ID1 ID2 ID3 ID4 KIAA2018 LYL1 MASH1 MATH2 MAX MESP1 MESP2 MIST1 MITF MLX MLXIP MLXIPL MNT MSC MSGN1 MXD1 MXD3 MXD4 MXI1 MYC MYCL1 MYCL2 MYCN MYF5 MYF6 MYOD1 MYOG NCOA1 NCOA3 NEUROD1 NEUROD2 NEUROD4 NEUROD6 NEUROG1 NEUROG2 NEUROG3 NHLH1 NHLH2 NPAS1 NPAS2 NPAS3 NPAS4 OAF1 OLIG1 OLIG2 OLIG3 PTF1A SCL SCXB SIM1 SIM2 SOHLH1 SOHLH2 SREBF1 SREBF2 TAL1 TAL2 TCF12 TCF15 TCF21 TCF3 TCF4 TCFL5 TFAP4 TFE3 TFEB TFEC TWIST1 TWIST2 USF1 USF2 See also editBasic helix loop helix leucine zipper transcription factorsReferences edit PDB 1x0o Card PB Erbel PJ Gardner KH October 2005 Structural basis of ARNT PAS B dimerization use of a common beta sheet interface for hetero and homodimerization J Mol Biol 353 3 664 77 doi 10 1016 j jmb 2005 08 043 PMID 16181639 Murre C Bain G van Dijk MA Engel I Furnari BA Massari ME Matthews JR Quong MW Rivera RR Stuiver MH June 1994 Structure and function of helix loop helix proteins Biochim Biophys Acta 1218 2 129 35 doi 10 1016 0167 4781 94 90001 9 PMID 8018712 Littlewood TD Evan GI 1995 Transcription factors 2 helix loop helix Protein Profile 2 6 621 702 PMID 7553065 Massari ME Murre C January 2000 Helix loop helix proteins regulators of transcription in eucaryotic organisms Mol Cell Biol 20 2 429 40 doi 10 1128 MCB 20 2 429 440 2000 PMC 85097 PMID 10611221 Amoutzias Grigoris D Robertson David L Van de Peer Yves Oliver Stephen G 2008 05 01 Choose your partners dimerization in eukaryotic transcription factors Trends in Biochemical Sciences 33 5 220 229 doi 10 1016 j tibs 2008 02 002 ISSN 0968 0004 PMID 18406148 a b Lawrence Zipursky Arnold Berk Monty Krieger Darnell James E Lodish Harvey F Kaiser Chris Matthew P Scott Matsudaira Paul T 2003 08 22 McGill Lodish 5E Package Molecular Cell Biology amp McGill Activation Code San Francisco W H Freeman ISBN 0 7167 8635 4 a b Chaudhary J Skinner MK 1999 Basic helix loop helix proteins can act at the E box within the serum response element of the c fos promoter to influence hormone induced promoter activation in Sertoli cells Mol Endocrinol 13 5 774 86 doi 10 1210 mend 13 5 0271 PMID 10319327 a b Amoutzias Gregory D Robertson David L Oliver Stephen G Bornberg Bauer Erich 2004 03 01 Convergent evolution of gene networks by single gene duplications in higher eukaryotes EMBO Reports 5 3 274 279 doi 10 1038 sj embor 7400096 ISSN 1469 221X PMC 1299007 PMID 14968135 Ledent V Paquet O Vervoort M 2002 Phylogenetic analysis of the human basic helix loop helix proteins Genome Biology 3 6 research0030 1 doi 10 1186 gb 2002 3 6 research0030 PMC 116727 PMID 12093377 Cabrera CV Alonso MC Huikeshoven H 1994 Regulation of scute function by extramacrochaete in vitro and in vivo Development 120 12 3595 603 doi 10 1242 dev 120 12 3595 PMID 7821225 Murre C McCaw PS Vaessin H et al 1989 Interactions between heterologous helix loop helix proteins generate complexes that bind specifically to a common DNA sequence Cell 58 3 537 44 doi 10 1016 0092 8674 89 90434 0 PMID 2503252 S2CID 29339773 Ellenberger T Fass D Arnaud M Harrison SC April 1994 Crystal structure of transcription factor E47 E box recognition by a basic region helix loop helix dimer Genes Dev 8 8 970 80 doi 10 1101 gad 8 8 970 PMID 7926781 Ma PC Rould MA Weintraub H Pabo CO May 1994 Crystal structure of MyoD bHLH domain DNA complex perspectives on DNA recognition and implications for transcriptional activation Cell 77 3 451 9 doi 10 1016 0092 8674 94 90159 7 PMID 8181063 S2CID 44902701 Wharton KA Franks RG Kasai Y Crews ST December 1994 Control of CNS midline transcription by asymmetric E box like elements similarity to xenobiotic responsive regulation Development 120 12 3563 9 doi 10 1242 dev 120 12 3563 PMID 7821222 Wang GL Jiang BH Rue EA Semenza GL June 1995 Hypoxia inducible factor 1 is a basic helix loop helix PAS heterodimer regulated by cellular O2 tension Proc Natl Acad Sci U S A 92 12 5510 4 Bibcode 1995PNAS 92 5510W doi 10 1073 pnas 92 12 5510 PMC 41725 PMID 7539918 Grove C De Masi F et al 2009 A multiparameter network reveals extensive divergence between C elegans bHLH transcription factors Cell 138 2 314 27 doi 10 1016 j cell 2009 04 058 PMC 2774807 PMID 19632181 External links editPDOC00038 in PROSITE Basic Helix Loop Helix Transcription Factors at the U S National Library of Medicine Medical Subject Headings MeSH bHLH family Archived 2016 04 22 at the Wayback Machine at PlantTFDB Plant Transcription Factor Database Retrieved from https en wikipedia org w index php title Basic helix loop helix amp oldid 1188057632, wikipedia, wiki, book, books, library,
