Basic helix–loop–helix

A basic helix–loop–helix (bHLH) is a

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.^[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 a consensus sequence called an E-box, CANNTG.^[7] 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.^[8]

Examples

A phylogenetic analysis suggested that bHLH proteins fall into 6 major groups, indicated by letters A through F. ^[9] Examples of transcription factors containing a bHLH include:

Group A

• MyoD
• Myf5
• Beta2/NeuroD1
• Tal1
• proneural bHLH genes like
  p-CaMKII, and pSer(336)NeuroD
  .
• Neurogenins

Group B

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

Group C

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

• AhR
• BMAL-1-CLOCK
• HIF
• MOP5

Group D

• EMC

Group E

• HEY1 and HEY2

Group F

These proteins contain an additional COE domain

• EBF1

Regulation

Since many bHLH

• 1989: Murre et al. showed that dimers of various bHLH proteins bind to a short DNA motif (later called
  E-Box).^[11] This E-box consists of the DNA sequence CANNTG, where N can be any nucleotide.^[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 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.^[16]

Human proteins with helix–loop–helix DNA-binding domain

• Basic helix-loop-helix leucine zipper transcription factors

References