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bHLH structural motif of the AhR protein: two α helices (blue) connected by a loop (red)

A basic-helix-loop-helix (bHLH) is a protein structural motif that characterizes a family of transcription factors.

The motif is characterized by two α helices connected by a loop. Transcription factors including this domain are typically dimeric, each with one helix containing basic amino acid residues that facilitate DNA binding ^[1]. One helix is typically smaller and due to the flexibility of the 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 ^[2]. The canonical E-box is CACGTG (palindromic), however some bHLH transcription factors bind to different sequences, which are often similar to the E-box.

Examples of transcription factors containing a bHLH include:

• AhR
• BMAL-1-CLOCK
• C-Myc
• MyoD
• Pho4
• HIF
• NPAS1, MOP5
• Scl, also known as Tal1
• proneural bHLH genes like p-CaMKII, and pSer(336)NeuroD.

bHLH transcription factors are often important in development or cell activity. BMAL1-Clock 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.

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 while the other subunit is constituitively 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, aable to form heterodimers with proteins that have the bHLH structure and inactivate their abilities as transcription factors ^[3].

• 1989: Murre et al. could show that dimers of various bHLH proteins bind to a short DNA motif (later called E-Box)^[4]. This E-box consists of the DNA sequence CANNTG, where N can be any nucleotide ^[2].

1. ^ Lawrence Zipursky; Arnold Berk; Monty Krieger; Darnell, James E.; Lodish, Harvey F.; Kaiser, Chris; Matthew P Scott; Matsudaira, Paul T.. McGill Lodish 5E Package - Molecular Cell Biology & McGill Activation Code. San Francisco: W. H. Freeman. ISBN 0-7167-8635-4. 
2. ^ ^{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. PMID 10319327. 
3. ^ Cabrera CV, Alonso MC, Huikeshoven H (1994). "Regulation of scute function by extramacrochaete in vitro and in vivo". Development 120 (12): 3595–603. PMID 7821225. 
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. PMID 2503252. 

• MeSH Basic+Helix-Loop-Helix+Transcription+Factors

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