Basic helix–loop–helix
A basic helix–loop–helix is a protein structural motif that characterizes one of the largest families of dimerizing transcription factors. 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.
bHLH transcription factors are often important in development or cell activity. For one, 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.
Structure
The motif is characterized by two α-helices connected by a loop. In general, transcription factors 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 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. The canonical E-box is CACGTG, 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.Examples
A phylogenetic analysis suggested that bHLH proteins fall into six major groups, indicated by letters A through F. Examples of transcription factors containing a bHLH include:Group A
- MyoD
- Myf5
- Beta2/NeuroD1
- Scl, also known as Tal1
- proneural bHLH genes like p-CaMKII, and.
- Neurogenins
Group B
- MAX
- C-Myc, N-Myc
- TCF4
Group C
These proteins contain an additional COE domain
- EBF1
Regulation
History
- 1989: Murre et al. showed that dimers of various bHLH proteins bind to a short DNA motif. This E-box consists of the DNA sequence CANNTG, where N can be any nucleotide.
- 1994: Harrison's and Pabo's 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, including Single-minded and the aromatic hydrocarbon receptor.
- 1995: Semenza's group identifies hypoxia-inducible factor as a bHLH-PAS heterodimer that binds a related asymmetric E-box.
- 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.
Human proteins with helix–loop–helix DNA-binding domain