Abasic helix–loop–helix (bHLH) is aproteinstructural motif that characterizes one of the largest families of dimerizingtranscription 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 containbasicamino acid residues in order to facilitateDNA binding.[6]
bHLH transcription factors are often important in development or cell activity. For one, BMAL1-Clock (also calledARNTL) is a core transcription complex in the molecularcircadian clock. Other genes, likec-Myc andHIF-1, have been linked tocancer due to their effects on cell growth and metabolism.
The motif is characterized by twoα-helices connected by aloop. In general, transcription factors (including this type) aredimeric, each with one helix containingbasicamino acid residues that facilitateDNA 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 aconsensus sequence called anE-box, CANNTG.[7] The canonicalE-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]
A phylogenetic analysis suggested that bHLH proteins fall into six major groups, indicated by letters A through F.[9] Examples of transcription factors containing a bHLH include:
Since many bHLHtranscription 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 theDrosophilaextramacrochaetae protein, have the helix-loop-helix structure but lack the basic region, making them unable to bind toDNA on their own. They are, however, able to formheterodimers with proteins that have the bHLH structure, and inactivate their abilities as transcription factors.[10]
1989: Murre et al. showed that dimers of various bHLH proteins bind to a short DNA motif (later calledE-Box).[11] This E-box consists of theDNA sequence CANNTG, where N can be anynucleotide.[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 Masiet 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
^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.PMID16181639.
^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.PMID8018712.
^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.ISSN0968-0004.PMID18406148.
^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.
^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.PMID2503252.S2CID29339773.
^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.PMID8181063.S2CID44902701.
