Basic helix–loop–helix

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 basic amino acid residues that facilitate DNA binding.{{cite book |author1=Lawrence Zipursky |author2=Arnold Berk |author3=Monty Krieger |author4=Darnell, James E. |author5=Lodish, Harvey F. |author6=Kaiser, Chris |author7=Matthew P Scott |author8=Matsudaira, Paul T. |title=McGill Lodish 5E Package - Molecular Cell Biology & McGill Activation Code |publisher=W. H. Freeman |location=San Francisco |isbn=0-7167-8635-4 |date=2003-08-22 }} 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.{{cite journal |vauthors=Chaudhary J, Skinner MK |title=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 |journal=Mol. Endocrinol. |volume=13 |issue=5 |pages=774–86 |year=1999 |pmid=10319327 |doi=10.1210/mend.13.5.0271|doi-access=free }} 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.{{Cite journal|last1=Amoutzias|first1=Gregory D.|last2=Robertson|first2=David L.|last3=Oliver|first3=Stephen G.|last4=Bornberg-Bauer|first4=Erich|date=2004-03-01|title=Convergent evolution of gene networks by single-gene duplications in higher eukaryotes|journal=EMBO Reports|volume=5|issue=3|pages=274–279|doi=10.1038/sj.embor.7400096|issn=1469-221X|pmc=1299007|pmid=14968135}}

A phylogenetic analysis suggested that bHLH proteins fall into 6 major groups, indicated by letters A through F. {{cite journal |last1=Ledent |first1=V |last2=Paquet |first2=O |last3=Vervoort |first3=M |title=Phylogenetic analysis of the human basic helix-loop-helix proteins. |journal=Genome Biology |date=2002 |volume=3 |issue=6 |pages=research0030.1 |doi=10.1186/gb-2002-3-6-research0030 |pmid=12093377 |pmc=116727 |doi-access=free }} Examples of transcription factors containing a bHLH include:

• MyoD
• Myf5
• Beta2/NeuroD1
• Scl, also known as Tal1
• proneural bHLH genes like p-CaMKII, and {{proper name|pSer(336)NeuroD}}.
• Neurogenins

• MAX
• C-Myc, N-Myc
• TCF4 (Transcription Factor 4)

These proteins contain two additional PAS domains after the bHLH domain.

• AhR
• BMAL-1-CLOCK
• HIF
• NPAS1, NPAS3, MOP5

• EMC

• HEY1 and HEY2

These proteins contain an additional COE domain

• EBF1

Since many bHLH transcription factors are heterodimeric, 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.{{cite journal |vauthors=Cabrera CV, Alonso MC, Huikeshoven H |title=Regulation of scute function by extramacrochaete in vitro and in vivo |journal=Development |volume=120 |issue=12 |pages=3595–603 |year=1994 |doi=10.1242/dev.120.12.3595 |pmid=7821225 |doi-access=free }}

• 1989: Murre et al. showed that dimers of various bHLH proteins bind to a short DNA motif (later called E-Box).{{cite journal |author=Murre C |title=Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence |journal=Cell |volume=58 |issue=3 |pages=537–44 |year=1989 |pmid=2503252 |doi=10.1016/0092-8674(89)90434-0 |name-list-style=vanc|author2=McCaw PS |author3=Vaessin H |display-authors=3 |last4=Caudy |first4=M. |last5=Jan |first5=L.Y. |last6=Jan |first6=Y.N. |last7=Cabrera |first7=Carlos V. |last8=Buskin |first8=Jean N. |last9=Hauschka |first9=Stephen D.|s2cid=29339773 }} This E-box consists of the DNA sequence CANNTG, where N can be any nucleotide.
• 1994: Harrison's{{cite journal |vauthors=Ellenberger T, Fass D, Arnaud M, Harrison SC | title = Crystal structure of transcription factor E47: E-box recognition by a basic region helix-loop-helix dimer | journal = Genes Dev. | volume = 8 | issue = 8 | pages = 970–80 |date=April 1994 | pmid = 7926781 | doi = 10.1101/gad.8.8.970| doi-access = free }} and Pabo's{{cite journal |vauthors=Ma PC, Rould MA, Weintraub H, Pabo CO | title = Crystal structure of MyoD bHLH domain-DNA complex: perspectives on DNA recognition and implications for transcriptional activation | journal = Cell | volume = 77 | issue = 3 | pages = 451–9 |date=May 1994 | pmid = 8181063 | doi =10.1016/0092-8674(94)90159-7 | s2cid = 44902701 }} 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.{{cite journal |vauthors=Wharton KA, Franks RG, Kasai Y, Crews ST | title = Control of CNS midline transcription by asymmetric E-box-like elements: similarity to xenobiotic responsive regulation | journal = Development | volume = 120 | issue = 12 | pages = 3563–9 |date=December 1994 | doi = 10.1242/dev.120.12.3563 | pmid = 7821222 | doi-access = free }}
• 1995: Semenza's group identifies hypoxia-inducible factor (HIF) as a bHLH-PAS heterodimer that binds a related asymmetric E-box.{{cite journal |vauthors=Wang GL, Jiang BH, Rue EA, Semenza GL | title = Hypoxia-inducible factor 1 is a basic helix-loop-helix-PAS heterodimer regulated by cellular O2 tension | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 92 | issue = 12 | pages = 5510–4 |date=June 1995 | pmid = 7539918 | pmc = 41725 | doi = 10.1073/pnas.92.12.5510| bibcode = 1995PNAS...92.5510W | doi-access = free }}
• 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.{{cite journal |author=Grove C |title=A multiparameter network reveals extensive divergence between C. elegans bHLH transcription factors |journal=Cell |volume=138 |issue=2 |pages=314–27 |year=2009 |pmid= 19632181 |doi=10.1016/j.cell.2009.04.058 |name-list-style=vanc|author2=De Masi F |display-authors=2 |last3=Barrasa |first3=M. Inmaculada |last4=Newburger |first4=Daniel E. |last5=Alkema |first5=Mark J. |last6=Bulyk |first6=Martha L. |last7=Walhout |first7=Albertha J.M. |pmc=2774807}}

AHR; 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.

• Basic helix-loop-helix leucine zipper transcription factors

{{Reflist|2}}

• [http://prosite.expasy.org/PDOC00038 PDOC00038] in PROSITE
• {{MeshName|Basic+Helix-Loop-Helix+Transcription+Factors}}
• [http://planttfdb.cbi.pku.edu.cn/family.php?fam=bHLH bHLH family] {{Webarchive|url=https://web.archive.org/web/20160422025922/http://planttfdb.cbi.pku.edu.cn/ |date=2016-04-22 }} at [http://planttfdb.cbi.pku.edu.cn PlantTFDB:Plant Transcription Factor Database]

{{Transcription factors|g1}}

{{DEFAULTSORT:Basic helix-loop-helix}}

Category:Protein domains

Category:Protein structural motifs

Category:DNA-binding substances