Basic-helix-loop-helix



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

Structure
The motif is characterized by two α helices connected by a loop. In general, transcription factors including this domain are dimeric, each with one helix containing basic amino acid residues that facilitate DNA binding. In general, one helix is 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. 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
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.

Regulation
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 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, able to form heterodimers with proteins that have the bHLH structure, and inactivate their abilities as transcription factors.

History

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